Triazole derivative

ABSTRACT

The invention relates to a triazole derivative with an activity inhibiting glycine transporter and for use as a pharmaceutical drug, and a novel triazole derivative. The inventive triazole derivative has an excellent activity inhibiting glycine transporter and is useful as a therapeutic agent of dementia, schizophrenia, cognitive disorders, or cognitive disorders involved in various diseases such as Alzheimer disease, Parkinson&#39;s disease, or Huntington disease or the like, or spasm involved in diseases such as nerve degenerative diseases and cerebrovascular disorders, or the like. Particularly, the pharmaceutical drug is useful for the amelioration of learning disability of dementia and the like.

This is a divisional of application Ser. No. 10/848,386 filed May 19,2004, now U.S. Pat. No. 7,034,047 which is a divisional of applicationSer. No. 10/276,720, filed Nov. 18, 2002, (abandoned), which is U.S.national stage application of PCT/JP01/04128, filed May 17, 2001. Theentire disclosures of the prior applications, application Ser. Nos.10/848,386, 10/276,720 and PCT/JP01/04128 are hereby incorporated byreference.

TECHNICAL FILED

The present invention relates to the pharmaceutical compositioncomprising triazole derivative as an effective ingredient, which isuseful as an inhibitor of the activity of glycine transporter, and anovel trizole derivative with an action as an inhibitor of the activityof glycine transporter.

BACKGROUND ART

Glycine is known as an excitatory and inhibitory neurotransmitter in thecentral and peripheral nervous systems. These functions work via twodifferent types of receptors, in which different types of glycinetransporter are independently involved. The function as a inhibitoryneurotransmitter works via the strychnine-sensitive glycine receptorpresent mainly in spinal cord and brain stem. Alternatively, thefunction as an excitatory neurotransmitter works via N-methyl-D-asparticacid (NMDA) receptor known as a subtype of glutamate receptors. Glycineis known as a coagonist for the NMDA receptor (Johnson J. W. and AsherP., Glycine potentiates the NMDA response in clutured mouse brainneurons, Nature, 325, 529–531, (1987)). The NMDA receptor is widelydistributed in brain, particularly in cerebral cortex and hippocampus.

Neurotransmitter transporter plays a significant role in the control ofthe concentration of neurotransmitter in the synaptic cleft, byincorporating the neurotransmitter inside the cells. Additionally, it isconsidered that neurotransmitter transporter makes a contribution to therecycling of neurotransmitter, by incorporating the neurotransmitterinto the presynapse terminus. It is considered that the control of thefunctions of neurotransmitter transporter is useful for therapeuticallytreating various diseased conditions due to abnormalities in nervefunctions, through the control of the concentration of neurotransmitterin the synaptic cleft.

Glycine transporter (GLYT) was first cloned in 1992 (Guastella J., etal., Cloning, expression and localization of a rat brain high-affinityglycine transporter, Proc. Natl. Acad. Sci., 89, 7189–93, 1992). Twotypes of the transporters, namely GLYT1 and GLYT2, have been identifiedso far (Liu Q. R., et al., Cloning and expression of a spinal cord- andbrain-specific glycine transporter with novel structural features, J.Biol. Chem., 268, 22802–8, 1993). Furthermore, a report tells that GLYT1has several splicing variants (Kim K. M., et al., Cloning of the humanglycine transporter type 1: molecular and pharmacologicalcharacterization of novel isoform variants and chromosomal localizationof the gene in the human and mouse genomes, Mol. Pharmacol., 45, 608–17,1994).

GLYT1 is expressed at a high density in spinal cord, brain stem,cerebellum, diencephalon and retina, while GLYT1 is expressed at a lowdensity in olfactory bulb and cerebral hemisphere. It is considered thatGLYT1 controls the NMDA receptor function (Smith K. E., et al., Cloningand expression of a glycine transporter reveal colocalization with NMDAreceptors, Neuron, 8, 927–35, 1992; Guastella J., et al., Cloning,expression, and localization of a rat brain high-affinity glycinetransporter, Proc. Natl. Acad. Sci., 89, 7189–93, 1992; and Bergeron,R., et al., Modulation of N-methyl-D-aspartate receptor function byglycine transport, Proc. Natl. Acad. Sci. USA, 95, 15730–15734, 1998).Javitt, et al. have reported that glycyldodecylamide (GDA) as a glycinetransporter inhibitor suppresses the enhancement of activity in mouse asinduced by phencyclidine (PCP) as an NMDA receptor antagonist (Javitt D.C., et al., Reversal of phencyclidine-induced hyperactivity by glycineand the glycine uptake inhibitor glycinedodecylaminde,Neuropsychopharmacology, 17, 202–4, 1997).

Alternatively, the expression of GLYT2 is limited to spinal cord, brainstem and cerebellum (Goebel D. J., Quantitative gene expression of twotypes of glycine transporter in the rat central nervous system, Mol.Brain Res., 40, 139–42, 1996; Zafra F., et al., Glycine transporters aredifferentially expressed among CNS cells, J. Neurosci., 15, 3952–69,1995). Thus, it is considered that GLYT2 is involved in the control ofthe function of strychnine-sensitive glycine receptor. It is suggestedthat the inhibition of GLYT2 induces the attenuation of paintransmission in spinal cord via the enhancing action ofstrychnine-sensitive glycine receptor function (Yaksh, T. L., Behavioraland autonomic correlates of the tactile evoked allodynia produced byspinal glycine inhibition: effects of modulatory receptor systems andexcitatory amino acid antagonists, Pain, 37, 111–123, 1989).

Furthermore, the enhancement of the strychnine-sensitive glycinereceptor function is useful for the therapeutic treatment of abnormalmuscular constraction such as spasm, myoclonus and epilepsy (Truong D.D., et al., Glycine involvement in DDT-induced myoclonus. MovementDisorders. 3,77–87, 1988; and Becker, C. M., et al., Disorders of theinhibitory glycine receptor: the spastic mouse, FASEB J. 4, 2767–2774,1990). Spasm has a relation with nerve disorders and damages such asepilepsy, cerebrovascular disorders, head injuries, multiple sclerosis,spinal injuries and dystonia.

It has been known that NMDA receptor has relations with various diseasedconditions. It is suggested that the functional deterioration of NMDAreceptor has a relation with schizophrenia (Javitt D. C. and Zukin S.R., Recent advances in the phencyclidine model of schizophrenia,American Journal of Psychiatry, 148, 1301–8, 1991). It is reported thatthe negative symptoms of schizophrenic patients are ameliorated with ahigh dose of glycine (Heresco-Levy U., et al., Double-blind,placebo-controlled, crossover trial of glycine adjuvant therapy fortreatment-resistant schizophrenia, Br J Psychiatry, 169, 610–7, 1996).

Additionally, the activation of NMDA receptor is involved in theformation of long-term potentiation (LTP) considered as a memory andlearning model at the neuron level (Collingridge G. L. and Bliss T. V.,NMDA receptors-their role in long-term potentiation. Trends. Neurosci.,10, 288–93, 1987). Still additionally, the administration of an NMDAreceptor antagonist to animals induces an amnesia therein (Morris R. G.,Andersen E., Lynch G. S. and Braudy M., Selective impairment of learningand blockade of long-term potentiation by an N-methyl-D-aspartatereceptor antagonist, AP5, Nature, 319, 774–6, 1986; and Mark J. Benvengaand Theodore C. Spaulding, Amnesic effect of the novel anticonvulsantMK-801, Pharmacol Biochem Behav., 30, 205–207, 1988). Hence, it issuggested that NMDA receptor plays a very significant role in memory andlearning.

Further, the deterioration of the function of NMDA receptor has beenreported even in humans, namely in patients with Alzheimer-type dementia(Ninomiya, H., et al., binding in human frontal cortex: decreases inAlzheimer-type dementia., J. Neurochem., 54, 526–32, 1990; and Tohgi,H., et al., A selective reduction of excitatory amino acids incerebrospinal fluid of patients with Alzheimer type dementia comparedwith vascular dementia of the Binswanger type., Neurosci. lett., 141,5–8, 1992).

Alternatively, a number of papers report an anti-amnesia action of aglycine-site agonist in animal models (Matsuoka N. and Aigner T. G.,D-Cycloserine, apartial agonist at the glycine site coupled toN-methyl-D-aspartate receptors, improves visual recognition memory inrhesus monkeys, J. Exp. Pharmacol. Ther., 278, 891–7, 1996; Ohno M., etal. Intrahippocampal administration of a glycine site antagonist impairsworking memory performance of rats. Eur. J. Pharmacol., 253, 183–7,1994; and Fishkin R. J., et al., D-cycloserine attenuatesscopolamine-induced learning and memory deficits in rats., Behav.Neural. Biol., 59, 150–7, 1993). These findings suggest that drugsinhibiting the activity of glycine transporter and thereby activatingthe function of NMDA receptor are useful as therapeutic agents ofdementia, schizophrenia and other cognitive disorders.

As the glycine transporter inhibitor, WO97/45115 disclosing tertiaryamins and WO97/45423 disclosing piperidine derivatives (TROPHIXPHARMACEUTICALS INC.), WO99/34790 disclosing amino acid derivatives andWO99/41227 disclosing tricyclic compounds (ALLELIX NEUROSCIENCE INC.),WO99/44596 and WO99/45011 disclosing piperidine derivatives (JANSSENPHARMACEUTICA N.V.), and WO00/07978 disclosing aminomethylcarbonatederivatives (AKZO NOBEL N.V.) are reported, other thanglycyldodecylamide (GDA). As 1,2,4-triazole derivatives, the followingcompounds are disclosed: DE4302051 (Dr. Karl Thomae G.m.b.h., platletaggregation inhibitory activity; Iran. J. Chem. Chem. Eng. (1998), 17,14 (A. Shafiee, et al., antibacterial and antifungal activities),DE3808283 (Boehringer Ingelheim K G., platelet activation factorantagonistic activity), WO97/32873 (Pfizer Research and DevelopmentCompany N.V., NMDA receptor antagonistic activity), and DD251345 (VEBChemiekombinat Bitterfeld Ger. Dem. Rep., biocidal activity), Eur. J.Med. Chem. (1985), 20, 257(F. Clemence, et al., analgesic andanti-inflammation activity), Sci. Pharm. (1978), 46, 298 (A. A. B.Hazzaa, et al., anti-spasm action). However, there are no reports thatthese compounds inhibit glycine transporter activity.

Based on the background described above, the present inventors have madeinvestigations about compounds with potent inhibitory activity ofglycine transporter. Consequently, the inventors have found that aspecific type of triazole derivative has a potent inhibitory activity ofglycine transporter. Thus, the invention has been achieved.

DISCLOSURE OF THE INVENTION

The invention relates to a glycine transporter inhibitor which comprisesa triazole derivative represented by the following general formula (I)or a pharmaceutically acceptable salt thereof as the effectiveingredient:

(in the formula, the symbols represent the following meanings;Ring A:

-   (1) an aromatic carbon ring which may be substituted,-   (2) an aliphatic carbon ring which may be substituted and may be    condensed with benzene ring or hetero ring,-   (3) a5-membered hetero ring which may be substituted and contain one    or two nitrogen atoms as the hetero atoms composing the ring and may    contain one oxygen atom or sulfur atom as a hetero atom other than    the nitrogen atoms and may be condensed with benzene ring or-   (4) a 6-membered hetero ring which may be substituted and contain    one nitrogen atom as a ring atom and may contain one oxygen atom or    sulfur atom as a hetero atom other than the nitrogen atom and may be    condensed with benzene ring;-   Ring B or D may be the same or different and each represents    aromatic carbon ring which may be substituted, an aliphatic carbon    atom which may be substituted, or a hetero ring which may be    substituted.-   R: H, halogeno-lower alkyl, aryl which may be substituted, hetero    ring which may be substituted, cycloalkyl which may be substituted,    or -[Alk1]m-X-[Alk2]n-Y—R¹-   wherein R¹: H, OH, cyano, aryl which may be substituted, hetero ring    which may be substituted, cycloalkyl which may be substituted, or    lower alkoxyl;-   X: bond, oxygen atom, S(O)q, or —N(R²)—;-   Y: bond, —C(O)—, —C(O)—N(R³)—, -Z₁-Alk3-, or —N(R³)-Alk3—C(O)—, with    the proviso that R¹ represent other than OH and lower alkoxy, when Y    is bond;-   Alk1 or Alk2 may be the same or different and each represents lower    alkylene, lower alkenylene or lower alkynylene; and-   m or n may be the same or different and each represents 0 or 1 or    m+n=1, provided that X represents bond;-   Z₁: S(O) q , —N(R³)—, —C(O)— or —C(O)—N(R³)—;-   Alk3: lower alkylene;-   R² or R³: the same or different from each other and each represents    H or lower alkyl;-   q: 0, 1 or 2 may be)

Additionally, the invention relates to a pharmaceutical compositioncontaining a glycine transporter inhibitor represented by the generalformula (I) as the effective ingredient.

The invention furthermore relates to a novel triazole derivativerepresented by the following general formula (Ia) or a salt thereof.

(in the formula, the symbols represent the following meanings;Ring A′:

-   (1) the group represented by the formula:

-   (2) naphthalene which may be substituted with one or two    substituents selected from the group represented by Rf,-   (3) an aliphatic carbon ring which may be substituted with one or    two substituents selected from the group represented by Rf and which    may be condensed with benzene ring or hetero ring,-   (4) a 5-membered hetero ring which may be substituted with one or    two substituents selected from the group represented by Rf and    contain one or two nitrogen atoms as the hetero atoms composing the    ring and may contain one oxygen atom or sulfur atom as a hetero atom    other than the nitorogen atoms and may be condensed with benzene    ring; or-   (5) a 6-membered hetero ring which may be substituted with one or    two substituents selected from the group represented by Rf and which    contain one nitrogen atom as the ring atom and may contain one    oxygen atom or sulfur atom as a hetero atom other than the nitorogen    atom and may be condensed with benzene ring;-   Ring B′: benzene or nitrogen-containing monocyclic hetero ring; or-   Ring D′: benzene or hetero ring, provided that ring A′, B′ and D′    never simultaneously represents benzene ring;-   Ra: a halogeno-lower alkyl, a hetero ring which may be substituted,    cycloalkyl which may be substituted, or -[Alk1]m-X-[Alk2]n-Y—R¹    wherein-   R¹: H, OH, cyano, aryl which may be substituted, hetero ring which    may be substituted, cycloalkyl which may be substituted, or lower    alkoxyl;-   X: bond, oxygen atom, S(O)q, or —N(R²)—;-   Y: bond, —C(O)—, —C(O)—N(R³)—, -Z₁-Alk3-, or —N(R³)-Alk3—C(O)—, with    the proviso that R1 represent other than OH and lower alkoxy, when Y    is bond;-   Alk1 or Alk2 may be the same or different and each represents lower    alkylene, lower alkenylene, or lower alkynylene;-   m or n may be the same or different and each represents 0 or 1 or    m+n=1, provided that X represents bond;-   Z₁: S(O)q, —N(R³)—, —C(O)— or —C(O)—N(R³)—;-   Alk3: lower alkynylene;-   R² or R³: the same or different from each other and each represents    H, or lower alkyl;-   Rb: halogen atom, lower alkyl which may be substituted with the    following substituents, lower alkynyl, halogeno-lower alkyl, hetero    ring, hetero ring-O—, cyano, nitro, halogeno-lower alkyl-O—, lower    alkoxyl, —O-lower alkylene-N(R³)-lower alkylene-C(O)O—R⁶, Z₂—R⁶, or    Z₃—R⁷, the substituents of the lower alkyl: OH, cyano, lower    alkoxyl, amino which may be substituted with lower alkyl;-   Z₂: S(O)q, —N(R³)—, —C(O)—, —C(O)—N(R³)—, —N(R³)—C(O)—,    —C(O)—S(O)q-, —N(R³)—S(O)q-, or —C(O)O—;-   Z₃: —N(R³)—, or —N(R³)—C(O)—;-   R⁶: H, lower alkyl or aryl;-   R⁷: OH, or lower alkoxyl;-   p: 0 or 1;-   q: 0, 1 or 2;-   Rc: lower alkyl, or halogen atom;-   Rd or Re: the same or different from each other and each represents    H, halogen atom, lower alkyl, lower alkoxyl, OH, lower alkyl,    halogeno-lower alkyl, phenyl, halogeno-lower alkyl-O—, amino which    may be substituted with lower alkyl or —NR⁸C (O)—R⁹;-   R⁸or R⁹: the same or different from each other and each represents    H, or lower alkyl;-   Rf: a group represented by Rb, oxo group, or aryl, with the psoviso    that Rd represents other than H, when the ring A′ represents benzene    substituted with lower alkoxyl and the ring B′ represents benzene.

Additionally, the invention provides a novel triazole derivativerepresented by the following general formula (Ib) or a salt thereof.

(in the formula, the symbols represent the following meanings:

-   Ra, Rc or p: the same group as formula (Ia) described in the claim    3;-   Rb′: halogen atom, lower alkyl which may be substituted with the    following substituents, halogeno-lower alkyl, hetero ring, hetero    ring-O—, cyano, nitro, halogeno-lower alkyl-O—, lower alkoxyl,    —O-lower alkylene-N(R³)-lower alkylene-C(O)O—R⁶, —N(R³)—R⁷, Z₂′—R⁶,    or Z₃—R⁷;-   the substituents of the lower alkyl: OH, cyano, lower alkoxyl, amino    which may be substituted with lower alkyl;-   Z₂′: S(O)q, —C(O)—, —C(O)—N(R³)—, —N(R³)—C(O)—, —C(O)—S(O)q-,    —N(R³)—S(O)q-, —C(O)O;-   R³, Z₃, R⁶, R⁷ or q: the same group as formula (Ia) described in the    claim 3;-   Rd′: H, lower alkoxyl, OH or lower alkyl;-   Re′: H, halogen atom, lower alkoxyl, halogeno-lower alkyl,    halogeno-lower alkyl-O—, or NR⁸C(O)—R⁹;-   R⁸or R⁹: the same group as formula (Ia) described in the claim 3;    with the priviso that,-   (1). at least one of Rd′ or Re′ represents a group other than H,    when Ra is lower alkyl, p=0:-   Rb′ represents lower alkyl, lower alkoxyl or halogen atom; or Rd′    represents a group except for lower alkyl, provided that Re′ is H;-   (2). Rb′ represents a group other than lower alkyl or lower alkoxyl,    when Ra represents α-styryland Rd′ and Re′ represent H and p=0;-   (3). Rb′ represents a group other than lower alkyl, when Ra    represents 2-furyland Rd′ and Re′ represent H and p=0.)

The invention relates to a triazole derivative represented by thegeneral formula (Ia) or a salt thereof, wherein the ring B′ representsnitrogen-containing monocyclic hetero ring; the ring D′ is benzene ring;Rf is halogen atom, lower alkyl, lower alkoxyl, aryl, cyano, carbamoylor oxo group; more preferably, the ring B′ is pyridine ring; the ring D′is benzene ring; and the ring A′ is 2,1,3-benzooxadiazole, or benzenesubstituted with one or two substituents selected from lower alkyl,halogen atom or cyano; and

most preferably, the triazole derivative is

-   5-[4-(2,6-difluorophenyl)-5-isopropyl-4H-1,2,4-triazol-3-yl]-2-phenylpyridine;-   4-[3-isopropyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzooxadiazole;-   3-[3-(3-methoxypropyl)-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile;-   3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile;-   2-{3-[N-(2-methoxyethyl)-N-methylamino]-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl}benzonitrile;-   4-(2,1,3-benzooxadiazol-4-yl)-N-(2-methoxyethyl)-N-methyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-3-ylamine    or a salt thereof.    Additionally, the invention relates to a pharmaceutical composition    which comprises the triazole derivative of the general formula (Ia)    or (Ib) as an active ingredient.

The triazole derivative in accordance with the invention will further bedescribed.

The substituent as described in the phrase ‘which may be substituted’specifically includes those described below, unless otherwise stated.

Above mentioned substituted groups are represented by Rb′, Rf, Rd andRe, hetero ring groups bound via nitrogen atom, and the like.

Herein, the term ‘lower’ in the specification represents linear orbranched hydrocarbon chain with one to 6 carbon atoms.

Thus, the term ‘lower alkyl’ means monovalent saturated hydrocarbon,linear or branched, specifically including for example methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyland the like.

The term ‘lower alkynyl’ represents monovalent, linear or branchedunsaturated hydrocarbon with one or more triple bonds with 2 to 6 carbonatoms and with both the termini being of free atomic valence andspecifically includes ethynyl, 1-propionyl and the like.

The term ‘lower alkylene’ represents the saturated hydrocarbon ofdivalence and with both the termini being of free atomic valence.

The term ‘lower alkenylene’ represents divalent, linear or branchedunsaturated hydrocarbon with one or more double bonds with 2 to 6 carbonatoms and with both the termini being of free atomic valence andspecifically includes vinylene, propenylene and the like.

The term ‘lower alkynylene’ means divalent, linear or branchedunsaturated hydrocarbon with one or more triple bonds with 2 to 6 carbonatoms and with both the termini being of free atomic valence.

The term ‘lower alkoxyl’ specifically includes for example, methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy,pentyloxy, hexyloxy, and isohexyloxy and the like.

‘Halogen atom’ includes fluorine, chlorine, bromine and iodine.

‘Halogeno-lower alkyl’ means the lower alkyl substituted with one ormore halogen atoms, which is preferably trifluoromethyl andtrifluoroethyl.

‘Aromatic carbon ring’ includes benzene and naphthalene, while themonovalent aromatic carbon ring group is expressed as ‘aryl’.

‘Aliphatic carbon ring’ means 3- to 8-membered monocyclic saturatedhydrocarbon ring, while the monovalent group thereof is expressed as‘cycloalkyl’. Preferably, the ‘aliphatic carbon ring’ is cyclopropyl,cyclopentyl and cyclohexyl.

‘Aliphatic carbon ring which may be condensed with benzene ring’ meansan aliphatic carbon ring condensed with benzene ring and is bound viathe carbon atom on the aliphatic carbon ring to other groups.Preferably, the ring is indane and 1,2,3,4-tetrahydronaphthalene.

‘Aliphatic carbon ring which may be condensed with hetero ring’ meansthe aliphatic carbon ring condensed with the following hetero ring andis bound via the carbon atom on the aliphatic carbon ring to othergroups. Preferably, the ring is 5,6,7,8-tetrahydroquinoline.

‘Hetero ring’ means aromatic hetero ring, saturated hetero ring andunsaturated hetero ring.

‘Aromatic hetero ring’ means 5- or 6-membered monocyclic or condensedheteroaryl containing one to 3 hetero atoms selected from nitrogen atom,oxygen atom or sulfur atom and the aromatic hetero ring is bound via thecarbon atom or nitrogen atom in the ring to other groups. Preferably,the aromatic hetero ring includes furan, pyrrole, thiophen, pyrazole,thiazole, imidazole, pyridine, pyrimidine, pyrazine, quinoline,isoquinoline and quinoxaline rings and the like.

Herein, the hetero ring represented by Rb or Rb′ means those bound viathe carbon atom in the ring to benzene ring.

‘Saturated hetero ring’ means 5- or 6-membered, saturated hetero ringcontaining one to 3 hetero atoms selected from nitrogen atom, oxygenatom or sulfur atom and is bound via the carbon atom or nitrogen atom inthe ring to other groups. Preferably, the saturated hetero ring includespyrrolidine, piperidine, piperazine and morpholine rings and the like.

‘Unsaturated hetero ring’ means 5- or 6-membered, unsaturated heteroring containing double bond in the hetero ring, except for aromatichetero ring.

‘Nitrogen-containing monocyclic hetero ring’ means saturated or aromatic5- or 6-membered monocyclic hetero ring which essentially contains oneor more nitrogen atoms as the constitutional elements of the ring andmay contain one to 3 hetero atoms selected from oxygen atom or sulfuratom as other hetero atoms, in the ‘hetero ring’ described above and the‘nitrogen-containing monocyclic hetero ring’ is bound via the carbonatom or nitrogen atom in the ring to other groups. Preferably, thenitrogen-containing hetero atom is pyrrole, imidazole, pyrazole,triazole, tetrazole, thiazole, furazan, pyridine, pyrazine, pyrimidine,pyridazine, pyrrolidine, piperidine, piperazine, morpholine and thelike. More preferably, the nitrogen-containing monocyclic hetero ring is5- or 6-membered monocyclic hetero ring where the hetero atom as theconstitutional element of the ring is only nitrogen atom and containsone to 3 nitrogen atoms.

‘5-membered hetero ring which may contain one or 2 nitrogen atoms as thehetero atoms composing the ring and may contain one oxygen atom orsulfur atom as the hetero atom other than the nitrogen atoms and whichmay be condensed with benzene ring’ as represented by the item (4) forthe ring A means, among the hetero rings, a 5-membered hetero ring whichmay contain 2 or less nitrogen atoms as the constitutional atoms of thering and may contain one oxygen atom or nitrogen atom other than theatoms, as well as the 5-membered hetero ring in condensation withbenzene ring.

The 5-membered hetero ring includes thiazole, furan, pyrrole, imidazole,pyrazole, furazan, thiadiazole, pyrazolidine, benzoimidazole,benzofuran, benzooxadiazole, benzothiadiazole, indole, isoindole,indazole and the like.

‘6-membered hetero ring which may contain one nitrogen atom as the ringatom and may contain one oxygen atom or sulfur atom as a hetero atomother than nitrogen atom and which may be condensed with benzene ring’as represented by the item (4) for the ring A means, among the heterorings, a 6-membered hetero ring which may contain nitrogen atom withinone in number as the ring-composing atom and may contain one oxygen atomor sulfur atom other than the atom described above-mentioned the heteroring, as well as the 6-membered hetero ring in condensation with benzenering.

The 6-membered hetero ring includes morpholine, pyridine, piperidine,quinoline, isoquinoline, 1,2-dihydroisoquinoline and1,2,3,4-tetrahydroisoquinoline.

The compound for use as the effective ingredient of the pharmaceuticalcomposition of the invention can sometimes form a salt with an inorganicacid or an organic acid. The salt thereof has an action to inhibit theactivity of glycine transporter. The preferable salt includes forexample salts thereof with mineral acids such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid orphosphoric acid or the like; salts thereof with organic acids such asformic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,tartaric acid, citric acid, carbonic acid, glutamic acid, aspartic acid,methanesulfonic acid or ethanesulfonic acid or the like; salts thereofwith inorganic bases such as sodium, potassium, magnesium, calcium oraluminum or the like; salts thereof with organic bases such asmethylamine, ethylamine or ethanolamine or the like; and salts thereofwith basic amino acids such as lysine or ornithine or the like.Additionally, the compound can form tertiary ammonium salt when thecompound reacts with lower alkyl halide, lower alkyl triflate, loweralkyl tosylate or benzyl halide or the like. As such tertiary ammoniumsalt, the salt of the compound with methyl iodide or benzyl chloride orthe like is preferable.

The compound for use as the effective ingredient in the pharmaceuticalcomposition of the invention includes optical isomers based on theasymmetric carbon atoms, geometric isomers based on the double bonds orcyclohexane ring, and atropeisomers occurring due to the inhibition ofthe rotation around a certain single bond. When two or more asymmetriccarbon atoms are present, furthermore, the compound includesdiastereomers. These various types of isomers isolated and mixtures ofthese isomers are also encompassed within the scope of the invention.Furthermore, the compound of the present invention includes hydrates,various solvates and tautomeric isomers. Still further, the compound foruse as the effective ingredient of the inventive pharmaceuticalcomposition includes compounds of crystal polymorphism. All thesecrystal forms are also encompassed within the scope of the compound foruse as the effective ingredient of the pharmaceutical composition of theinvention.

Further, the compound of the present invention includespharmacologically acceptable prodrugs. The group forming thepharmaceutically acceptable prodrugs of the compound of the presentinvention includes the group described in Prog. Med. 5; 2157–2161 (1985)and the group described in “Development of pharmaceutical products”,Vol. 7, Molecular designing, pp. 163–198, Hirokawa Shoten, 1990. Morespecifically, the group can be converted to the primary amine, secondaryamine, OH or COOH group, through hydrolysis or solvated decomposition orunder physiological conditions and include for example lower alkylene—COOR (R represents H or lower alkyl; the same is true hereinbelow)which may be substituted with —OCO—, lower alkenylene-COOR which may besubstituted with —OCO—, aryl which may be substituted with —OCO—,—OCO-lower alkylene-O-lower alkylene-COOR, —OCO—COR, lower alkyl whichmay be substituted with —OCO—, lower alkylene-COOR which may besubstituted with —OSO₂—, —O-futazyl,

5-methyl-1,3-dioxolen-2-on-4-yl-methyloxy.

Herein, the following compounds are included among preferable examplesof known compounds encompassed within the invention of use. For example,the following compounds among the compounds disclosed in Japanese PatentLaid-open No. 2000–63363 are included:

-   2-[3-(biphenyl-4-yl)-5-methyl-4H-1,2,4-triazol-4-yl]phenol,-   3-(biphenyl-4-yl)-4-(2-ethoxyphenyl)-5-methyl-4H-1,2,4-triazole,-   3-(biphenyl-4-yl)-5-methyl-4-(2-propoxyphenyl)-4H-1,2,4-triazole,-   3-(biphenyl-4-yl)-5-ethyl-4-(2-methoxyphenyl)-4H-1,2,4-triazole,-   4-(2-methoxyphenyl)-3-methyl-5-(2′-methylbiphenyl-4-yl)-4H-1,2,4-triazole    and-   3-(biphenyl-4-yl)-4-(2-iodophenyl)-5-methyl-4H-1,2,4-triazole.

Other than those described above, for example,

-   3-(biphenyl-4-yl)-5-(furan-2-yl)-4-phenyl-4H-1,2,4-triazole    (LTPBP42, CD-ROM catalog 1996),-   3-(biphenyl-4-yl)-4-(2-methoxyphenyl)-5-methyl-4H-1,2,4-triazole    (LTPBP20, CD-ROM catalog 1996) commercially available from LaboTest    Co. (Freiberg, Germany) and the like are also included.    (Production Process)

The production process of the compound in accordance with the inventionis now described below.

The objective 3,4,5-tri-substituted-1,2,4-triazole derivative can besynthetically prepared by the following processes. But the productionprocess of the compound of the present invention is not limited to them.

Production Processes Nos. 1 to 3

(In the formula, L¹ represents oxygen atom or sulfur atom; R¹⁰represents lower alkyl and the like. The remaining symbols represent thesame as described above. The same is true hereinbelow.)

At the production processes Nos. 1 to 3, the objective3,4,5-tri-substituted-1,2,4-triazole can be prepared in an almostsimilar fashion to the method described for example in the unexaminedpublication (Japanese Patent unexamined publication No. 2000–63363).

According to the production process No. 1, the objective3,4,5-tri-substituted 1,2,4-triazole derivative can be prepared bysubjecting acid hydrazide (1) commercially available or possiblyprepared by an almost similar method to the method described in JapanesePatent unexamined publication No. 2000–63363 and the compound (2) tonucleophilic substitution reaction and dehydration cyclarizationreaction.

According to the production process No. 2, the compound of the presentinvention can be prepared by subjecting the compound (4) possiblyprepared by an almost similar method to the method described in JapanesePatent Laid-open No. 2000–63363 and acid hydrazide (5) to nucleophilicsubstitution reaction and dehydration cyclarization reaction.

According to the production process No. 3, the compound of the presentinvention can be prepared by subjecting 1,3,4-oxadiazole (7) prepared bydehydration cyclarization reaction of diacylhydrazine (6) to reactionwith appropriate amine derivative (8).

Production Processes Nos. 4 and 5

(In the formula, L² and L³ represent halogen, alkyl- or aryl-sulfonyloxysuch as trifluoromethanesulfonyloxy, and phosphoryloxy substituted withlower alkoxy group; M¹ and M² represent metals such as magnesium, zinc,boron and tin and the like; M²-Q represents organic metal compounds andmetal halides, for example, described in the reference edited by TsujiJiro (Senikinzoku Ga Hiraku Yukigosei, p. 25–p. 37 (1997)) and the like;and B″ represents an aromatic carbon ring or aromatic hetero ring; andD″ represents an aromatic carbon ring or aromatic hetero ring.)

The 1,2,4-triazole derivative (11) with aromatic rings as the rings B″and D″ can be synthetically prepared, using the following productionprocesses Nos. 4 and 5, in addition to the production processes Nos. 1,2 and 3.

The production process No. 4 is a production process, utilizing thecross coupling reaction between compound of the present invention (9)with halogen or alkylsulfonyloxy as the substituent L² on the aryl orheteroaryl ring B″ and appropriate aryl metal or heteroaryl metalcompound (10). Additionally, the production process No. 5 is aproduction process, utilizing the cross coupling reaction between arylmetal or heteroaryl metal compound (13) prepared from 1,2,4-triazolederivative (9) and aryl or heteroaryl compound (14) with appropriatehalogen or alkylsulfonyl group.

The cross coupling reaction in the production processes Nos. 4 and 5 canbe performed in an appropriate solvent such as tetrahydrofuran andN,N-dimethylformamide in the presence of palladium compound or nickelcompound (for example, tetrakistriphenylphosphine palladium) and in thepresence or absence of abase, if necessary, under cooling or heating,using an aryl metal or heteroaryl metal compound (10 or 13) containingmagnesium, zinc, boron and tin and the like and an aryl or heteroarylcompound (9 or 14) with an appropriate halogen or an alkylsulfonyloxygroup as the raw materials.

Production Process No. 6

(In the formula, L⁵ represents an leaving group such as halogen and thelike and X represents NR² or oxygen atom.)

The 1,2,4-trizole derivative (19) with a substituent binding vianitrogen atom or oxygen atom at position 5 can also be prepared byconverting the 1,2,4-triazole derivative (16) synthetically prepared bythe production process No. 2 into the compound (17),for example,according to the method described by Walser, et al. (Journal ofHeterocyclic Chemistry, 12,717(1975)) and subjecting amine or alcoholderivative (18) to reaction without any solvent or in an appropriatesolvent (for example, xylene) in the presence or absence of anappropriate base at 50 to 200° C. for 2 to 72 hours.

Production Process No. 7

(In the formula, the base represents sodium hydroxide and the like; L⁴represents an leaving group such as halogen and the like.)

The 1,2,4-triazole derivative (24) with a substituent binding via sulfuratom at the position 5 can also be prepared, using acid hydrazide (1)commercially available or prepared by a similar method to the methoddescribed in Japanese Patent unexamined publication No. 2000-63363 as araw material, for example according to the method of Maxwell, et al.(Journal of Medicinal Chemistry, 27, 1565 (1984)).

As described above, the compound of the present invention includesisomers such as racemic compounds, optically active compounds anddiastereomers and the like, being present singly or in mixture. Theracemic compounds can be introduced into stereochemically pure isomers,using appropriate raw material compounds or by general racemicresolution processes (for example, a process of optical resolution,comprising introducing the raw material compounds into diasteromer saltswith general optically active acids (tartaric acid, etc.)).Additionally, diastereomer mixtures can be separated by general methods,for example fractional crystallization or chromatography or the like.

PHARMACOLOGICAL TESTS

The pharmacological actions of the compound of the present invention aredescribed hereinbelow.

The action of the compound of the present invention to inhibit theactivity of the glycine transporter was verified by the following testmethods.

1. Action of Inhibiting Glycine Transporter

(Cell Culture)

C6 glioma cell expressing GLYT1 subtype of the glycine transporter (seeGomeza-J., Zafra-F., Olivares-L., Gimenez-C., Aragon-C., Regulation byphorbol esters of the glycine transporter (GLYT1) in glioblastomacells., Biochim-Biophys-Acta., 1233, 41–46 (1995)) was used.

C6 glioma cell (American Type Culture Collection) was cultured in DMEMcontaining 10% fetal bovine serum, 100 units/ml penicillin G and 0.1mg/ml streptomycin sulfate in a CO₂ incubator under conditions of 5% CO₂and 37° C.

([³H]-glycine Uptake Assay)

[³H]-glycine uptake was performed by the method of Gomeza, et al.

C6 glioma cells were plated out at a concentration of 2×10⁴ cells/wellin a 96-well plate (Culturplate, Packard Co.), for culturing for 2 days.Subsequently, [³H]-glycine uptake was tested. The cell was rinsed oncein a buffer (150 mM NaCl, 5 mM KCl, 1 mM CaCl₂, 1 mM MgCl₂, 10 mMglucose, 5 mM L-alanine, 10 mM Hepes-Na, pH 7.4), followed by subsequentaddition of the buffer, for incubation at 37° C. for 10 minutes.

After incubation, the buffer was exchanged to a reaction bufferincluding [³H]-glycine (about 0.2 μM, 41 Ci/mmol, New England Nuclear)and a compound to be assessed, for incubation at 37° C. for another 20minutes. After 20-min reaction, the reaction mixture was rinsed inice-cold PBS (phosphate buffered saline). The cell was dissolved in 0.1NNaOH solution, to assay the radioactivity incorporated with a liquidscintillation counter. The specific incorporation was defined as aportion substituted with 3 mM sarcosine in the total incorporation. Thetest compound was assessed by determining the incorporation-inhibitingratio of the specific incorporation.

Consequently, the compound of the present invention was verified to havean action to inhibit [³H]-glycine incorporation.

GLYT-inhibiting activity Test compound IC50(μM) Compound 1 1.0 Compound2 4.6 Compound 3 0.35 Production Example 1 0.36 Example 1 0.14 Example 20.10 Example 5 0.41 Example 6 0.26 Example 8 0.25 Example 9 0.33 Example10 0.20 Example 112 1.0 Example 157 1.5 Example 202 1.6 Example 236 0.94Example 256 0.086 Example 279 4.6Compound 1:

-   3-(biphenyl-4-yl)-4-(2-methoxyphenyl)-5-methyl-4H-1,2,4-triazole    (Japanese Patent unexamined uplication No. 2000-63363; Example 33)    Compound 2:-   3-(biphenyl-4-yl)-5-(furan-2-yl)-4-phenyl-4H-1,2,4-triazole (LTPBP42    CD-ROM catalog 1996 of LaboTest Co. (Freiberg, Germany))    Compound 3:-   3-(biphenyl-4-yl)-5-ethyl-4-(2-methoxyphenyl)-4H-1,2,4-triazole    (Japanese Patent unexamined publication No. 2000-63363; Example 23)    2. Experimental Method of (+)-HA966-Induced Enhancement of Activity    in Mouse

the method reported previously (J. Neural Transm., 97: 175–185, 1994)was used for carrying out the experiment with modification.

-   Animal: male ICR mouse (Nippon SLC; age 5 to 7 weeks)-   Chemical drug: reserpine (Apoplon Injection of 1 mg/ml; manufactured    by Daiichi Pharmaceuticals Co., Ltd.), (+)-HA966 (Proc. Nat. Acad.    Sci. U.S.A., 87, 347–351, 1990), α-methyl-para-tyrosine methyl ester    (Sigma, Inc.).-   Experimental Apparatus: Supermex (Muromachi Machine)    Experimental Method-   (1) Pharmaceutical drug-treated groups were defined as follows.-   (16 mice per one group were used for the experiment).-   (ACSF+Vehicle) group-   {(+)-HA966 80 μg/mouse icv+Vehicle} group-   {(+)-HA966 80 μg/mouse icv+test compound} group-   (2) 19 hours before (+)-HA966 administration, reserpine (10 mg/kg)    was dosed intraperitoneally.-   (3) 0.5 hour before (+)-HA966 administration, α-methyl-para-tyrosine    methyl ester (250 mg/kg) was intraperitoneally administered.-   (4) 20 minutes before (+)-HA966 administration, a test compound was    orally given.-   (5) (+)-HA966 was acutely administered bilaterally into the lateral    ventricule (with free hands using 2-step needle); immediately    thereafter, each animal was placed in the measuring cage of an    activity measurement apparatus.-   (6) Immediately thereafter, the activity per one hour was measured.-   (7) The integral value of the activity per one hour was selected as    the data. The effect was determined as follows. The enhancement of    the activity due to (+)-HA966 {difference between    ((+)-HA966+Vehicle)administration group and    (ACSF+Vehicle)administration group} was defined as 100%. And the    activity in a pharmaceutical drug-treated group {difference between    ((+)-HA966+test conpund)administration group and (ACSF+test    compound)administration group} was normalized. It was calculated by    following formula. When the normalized activity was below 50%, the    test compound was judged to have the effect.    The formula used for standardization    {activity of ((+)-HA966+test conpund)administration group−activity    of (ACSF+test compound)administration group}÷{activity of    ((+)-HA966+Vehicle)administration group−activity of    (ACSF+Vehicle)administration group}×100(%)

When the compound shown in the Production Example 1 was orally given at10 mg/kg, the activity was at 43%.

3. (+)-HA966-Induced Learning Disability (Mouse Passive Avoidance Test)

Animal: male ddY mouse (Nippon SLC; age 7 to 9 weeks at training) wasused. 16 to 32 animals were used per one group.

<Experimental Procedures>

Preparation of Pharmaceutical Drugs

-   (1) A test compound for oral administration was suspended in aqueous    0.5% methyl cellulose solution, and for intraperitoneal    administration was suspended in solution dissolved 0.5% of methyl    cellulose solution in saline (hereinafter referred to as 0.5% methyl    cellulose solution). The administration volume was 10 ml per 1    kg·body weight. As a placebo of the test compound, 10 ml per 1    kg·body weight of aqueous 0.5% methyl cellulose solution for oral    administration and 10 ml of aqueous 0.5% methyl cellulose solution    (herein referred to as vehicle) for intraperitoneal administration    (herein referred to as vehicle) was administrated.-   (2) (+)-HA966 was dissolved in artificial cerebrospinal fluid    (ACSF). The administration volume was 4 μl per one mouse. As a    vehicle of (+)-HA966, 4 μl of ACSF was dosed per one mouse.    Intracerebral Cannula Apparatus

7 to 14 days before the initiation of training, a cannula forintracerebroventricular administration was inplanted to the animalsunder anesthesia.

Training

-   (1) On day 1 at the learning experiment, the mice were acclimated in    an experimental room for one hour or longer.-   (2) A test compound or the vehicle was orally or intraperitoneally    given.-   (3) 20 minutes thereafter, (+)-HA966 was administered at 60 μg    intracerebroventriculally.-   (4) 15 minutes after the dosing of (+)-HA966, the each mouse was    placed in the bright room of the experimental apparatus of the    passive avoidance reaction test, where the mouse was left for 30    seconds. Subsequently, the guillotine door was opened. When the mice    entered in the dark room, the mice were exposed to an electric shock    at an intensity of 60V and a delay of 1 sec for a duration of 2 sec.    When the mice thus returned to the bright room, the guillotine door    was closed. Then, the mice were left in the bright room for 30    seconds.-   (5) The mice were taken out to be back to the home cage.-   (6) After the termination of the training, the mice were left to    stand in the experimental room and were then back to the feeding    room.    Test (24 Hours after the Training)-   (1) The animals were left in the experimental room for one hour or    longer.-   (2) After the mice were placed in the bright room and left for 30    seconds, the guillotine door was opened.-   (3) The time (step-through latency) required for the mice to cross    the sensor of the dark room from the opening of the guillotine door    was counted. The longest time for the measurement was 300 seconds.-   (4) The step-through latency was adopted as an indicator of learning    ability. The learning disability due to (+)-HA966 was compared    between the two groups, namely (ACSF+Vehicle) group and    {(+)-HA966+Vehicle} group by the Wilcoxon rank sum test. The action    of an assessment compound on the improvement of leaning disability    was compared between many groups, namelyf{(+)-HA966+Vehicle} group    and {(+)-HA966+assessment compounds} groups by the two-tailed Steel    test. A significance was determined at p<0.05.

The compound shown in the Production Example 1 as dosedintraperitoneally was at the minimum effective dose of 3 mg/kg.

4. Electric Convulsion Shock (ECS)-Induced Learning Disability (MousePassive Avoidance Test)

With reference to the previous report (Eur J Pharmacology, 321; 273–278,1997), assessment was done as follows.

-   Animal: male ddY mouse (Nippon SLC; age 5 weeks at training) was    used. 16 animals were used per one group.    <Experimental Procedures>    Preparation of Chemical Agents-   A test compound for oral administration was suspended in aqueous    0.5% methyl cellulose solution, and for intraperitoneal    administration was suspended in solution dissolved 0.5% of methyl    cellulose solution in saline The dose administered was 10 ml per 1    kg·body weight. As a placebo of the test compound, 10 ml of aqueous    0.5% methyl cellulose solution for oral administration and 10 ml of    0.5% methyl cellulose solution in saline for intraperitoneal    administration (herein referred to as vehicle) was administrated.    Training-   (1) On day 1 at the experiment, the mice were left in an    experimental chamber for one hour or longer.-   (2) The mice were placed in the bright room of the experimental    apparatus of the passive avoidance test, where the mice were left to    stand for 30 seconds. Subsequently, the guillotine door was opened.    When the mice entered in the dark room, the mice were exposed to an    electric shock at an intensity of 60V and a delay of 1 sec for a    duration of 2 sec. When the mice thus returned to the bright room,    the guillotine door was closed. Then, the mice were left to stand in    the bright room for 30 seconds.-   (3) The mice were taken out. An electrode was attached on both the    ears immediately (within one minute), to give ECS (electric    convulsion shock).-   (4) A test compound was administered orally or intraperitoneally.-   (5) The mice were back to the home cage.-   (6) After the termination of the training, the mice were left in the    experimental room for 60 minutes or longer and were then back to the    feeding room.    Test (24 Hours after the Training)-   (1) The animals were left in the experimental room for one hour or    longer.-   (2) After the mice were placed in the bright room and left for 30    seconds, the guillotine door was opened.-   (3) The time (step-through latency) required for the mice to cross    the sensor of the dark room from the opening of the guillotine door    was counted. The longest time for the measurement was 600 seconds.-   (4) The step-through latency was adopted as an indicator of learning    ability. The learning disability due to ECS was compared between the    two groups, namely (ECS−no load+Vehicle) group and (ECS    load+Vehicle) group by the Wilcoxon rank sum test. The action of a    test compound on the improvement of leaning disability was compared    between many groups, namely (ECS load+Vehicle) group and (ECS    load+assessment) compounds groups by the two-tailed Steel test. A    significance was determined at p<0.05.

The compound shown in the Production Example 1 as dosedintraperitoneally was at the minimum effective dose of 10 mg/kg.

5. Action of Assessment Compound on Learning Disability in Aged Rat(Water Maze Task).

[Experimental method]

The experimental protocol was defined as follows, with reference to themethod of Baxter M., et al. (Neurobiol. Aging 15, 207–213, 1994).

Male F344 rats (Nippon Charles River) of age 24±1 months (aged rats)were used at the experiment. Water (25° C.) was charged in a circle poolof a diameter of 130 cm and a height of 40 cm to a depth of 25 cm, inwhich a plastic platform of a diameter of 10 cm and a height of 24 cmwas arranged to a depth of about 1 cm below the water surface. Duringthe test, water in the pool was made completely opaque, using black ink.

-   Handling: 3-min handling was carried out twice for all the rats,    prior to the experiment.-   Shaping: a platform was placed in an alley with a 15-cm width, a    35-cm height (from the water surface) and a 100-cm length. Black    opaque water was charged therein so as to place the platform to a    depth of about 1 cm below the water surface. The platform was placed    the end of the alley. Each rat was placed at a specific place in the    alley, allowed to reach the platform. Three successive start    locations, each transfer away from the platform, were used; (a) on    the platform, (b) with forepaws om the platform, (c) approximately    25 cm from the platform. After the rat climbs on the platform, the    rat is retained there for about 10 seconds.-   Straight swim: rats are placed on the end of the alley (the opposite    side of the platform), to allow the rats to swim three times. When    the rats reach the platform, the rats are retained on the platform    for about 10 seconds. The latency until the rats reach the platform    is recorded.-   Acquisition task: rats are gently placed in water, while the rats    face on the pool wall so as to subject the rats to acquisition trial    at 5 times/day at maximum for the longest duration of 8 days. The    latency until the rats reach the platform is recorded with a color    video tracking system (Compact VAS) on a computer system. The    duration per one trial is set to 60 seconds at maximum. When the    rats cannot find the platform within 60 seconds, the experimental    person allows the rats to climb the platform. The rats are retained    on the platform within about 10 seconds. The trial interval is set    to about 2 minutes. The start position (at 7 sites) should be    changed every trial in a random manner. For the acquisition trial,    40 trials in total are carried out at maximum. On the first day, the    rats are allowed to swim with no dosing of any drug, so as to group    the rats evenly on the basis of the latency period. Thereafter, a    test compound or the vehicle is dosed for 7 days, to measure the    latency period.-   Transfer task: about 4 hours after the last trial, 50-sec transfer    task is conducted in the absence of platform. Swim time on the    targeted quadrant (quadrant of the pool where the platform was    present at acquisition task) was measured.-   Treatment with pharmaceutical drug: a test compound is suspended in    0.5% MC physiological saline. The pharmaceutical drug and the    vehicle of 1 mg/kg were administered intraperitoneally 30 minutes    prior to the training. No administration prior to the transfer task.

Using the latency at the acquisition task and the time period in whichthe rats are retained in the target quadrant of the transfer task asmarkers, the difference between the test compound and the vehicle iscompared by two-way ANOVA or Student t-test.

The efficucy of the compound of present invention on the learningimpairment in aged rats can be verified using the water maze

Additionally, the efficacy of the compound of the present invention onthe learning impairment in aged rats can be verified, using as theobject recognition test, as shown in for example the previous report(Pharmacological Research, 36(6); 463–469, 1997).

A pharmaceutical composition containing one or two or more types of thecompound represented by the general formula (I) and the pharmaceuticallyacceptable salt thereof or hydrate thereof as the effective ingredientcan be prepared into tablets, powders, fine granules, granules,capsules, pills, liquids, injections, suppositories, ointments, and papsand the like, using carriers and excipients for general use forformulation, and other additives. The resulting formulations are orallyor parenterally given.

The clinical dose of the compound of the present invention to humans isappropriately determined, depending on the symptom, age, sex and bodyweight of an individual patient, to which the compound of the presentinvention is applied. Generally, the compound of the present inventionis orally given at 0.1 to 500 mg per one adult per day in one portion ordivided portions. Because the dose varies under various conditions, adose below the range of the dose may sometimes be sufficient.

As the solid composition for oral administration in accordance with theinvention, tablets, powders and granules are used. For such solidcomposition, one or more active substances are mixed with at least oneinactive diluent, for example lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrdlidone,metasilicate aluminate magnesium and the like.

According to general methods, the composition may satisfactorily containadditives other than inactive diluents, for example lubricants such asmagnesium stearate, disintegrators such as cellulose calcium glycolate,stabilizers such as lactose, solubilization or dissolution-auxiliaryagents such as glutamic acid or aspartic acid. If necessary, the tabletsor pills may be coated with films of substances dissolvable in stomachor intestine, such as sucrose, gelatin, hydroxypropyl cellulose andhydroxypropylmethyl cellulose phthalate and the like.

The liquid composition for oral dosing contains pharmaceuticallyacceptable emulsifiers, solubilizers, suspending agents, syrups, andelixirs and the like and contains inactive diluents for general use, forexample distilled water and ethyl alcohol. The composition maysatisfactorily contain auxiliary agents such as solubilization- ordissolution-auxiliary agents, moisturizers and suspending agents,sweeteners, flavoring agents, aromatic agents and preservatives.

The injections for parenteral dosing encompass aseptic, aqueous ornon-aqueous solubilizers, suspending agents and emulsifiers. Thediluents of aqueous solubilizers and suspending agents include forexample distilled water for injections and physiological saline.Water-insoluble solubllizers and suspending agents include for examplepropylene glycol, polyethylene glycol, vegetable oils such as olive oil,alcohols such as ethyl alcohol, surfactants such as polysorbate 80(trade name). Such composition may satisfactorily contain additivesincluding isotonic agents, preservatives, moisturizers, emulsifiers,dispersants, stabilizers (for example, lactose), and solubilization- anddissolution-auxiliary agents (for example, glutamic acid and asparticacid). These may be sterilized by filtration through for example filterwith bacteria retained thereon, blending with sterilizers orirradiation. These may be prepared into aseptic solid compositions. Theresulting aseptic compositions are used, after dissolution in asepticwater or aseptic solvents for injections prior to use.

EXAMPLES

As to the novel compound of the invention, the invention is nowdescribed in more detail in the following Production Examples andExamples. Herein, the invention is not limited to these compounds alone.Further, the raw materials for use in accordance with the invention aredescribed in Reference Examples, in case that the raw materials arenovel.

Reference Example 1 N-(2-Fluorophenyl)-2-methylthiopropionimidate methylester

-   (1) 2-Fluoroaniline (5.07 g) and triethylamine (9.54 ml) were    dissolved in tetrahydrofuran (50 ml), followed by addition of a    solution of isobutyryl chloride (5.02 ml) in tetrahydrofuran (20 ml)    under ice cooling, and stirred at ambient temperature for 4 hours.    After the reaction solution was concentrated under reduced pressure,    water (200 ml) was added to the resulting residue, and stirred at    ambient temperature for one hour. The resulting solid was filtered    and washed with water, to afford N-(2-fluorophenyl)isobutylamide in    pale yellow solid (7.08 g, 86%). The physicochemical values are as    follows.

¹H-NMR (CDCl₃) δ: 1.28 (6H, d, J=6.8 Hz), 2.50–2.64 (1H, m), 6.99–7.15(3H, m), 7.37 (1H, brs), 8.32–8.38 (1H, m).

-   (2) N-(2-Fluorophenyl)isobutylamide (7.08 g) was dissolved in    toluene (90 ml), followed by addition of the Lawesson reagent (8.15    g), and refluxed under heating for one hour. After the reaction    solution was cooled to ambient temperature, the solution was    concentrated under reduced pressure. The resulting residue was    purified by silica gel column chromatography (eluent: n-hexane/ethyl    acetate=9/1), to afford N-(2-fluorophenyl)thioisobutylamide as    yellow oil (7.74 g, quantitative). The physico-chemical values are    as follows.

¹H-NMR (CDCl₃) δ: 1.37 (6H, d, J=6.8 Hz), 2.94–3.08 (1H, m), 7.11–7.25(3H, m), 8.53–8.65 (2H, m).

-   (3) N-(2-Fluorophenyl)thioisobutylamide (7.71 g) was dissolved in    acetonitrile (150 ml), followed by addition of potassium carbonate    (16.2 g) and methyl iodide (7.30 ml), and stirred at 50° C. for 30    minutes. After the reaction solution was cooled to ambient    temperature, the resulting solution was concentrated under reduced    pressure. To the resulting residue were added water (100 ml) and    saturated aqueous sodium chloride (200 ml), and extracted with ethyl    acetate. The organic layer was dried over anhydrous magnesium    sulfate, and the solvent was evaporated under reduced pressure.    Subsequently, the resulting residue was purified by silica gel    column chromatography (eluent: n-hexane/ethyl acetate=20/1), to    afford the entitled compound    N-(2-fluorophenyl)-2-methylthiopropionimidate methyl ester as pale    yellow oil (7.84 g, 95%). The physico-chemical values are as    follows.

¹H-NMR (CDCl₃) δ: 1.16 (6H, brs), 2.38 (3H, s), 2.81–2.96 (1H, m),6.74–6.80 (1H, m), 6.95–7.09 (3H, m).

Production Example 13-Biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole

N-(2-Fluorophenyl)-2-methylthiopropionimidate methyl ester (7.84 g)prepared in the Reference Example 1 and biphenyl-4-carboxylic acidhydrazide (5.25 g) were dissolved in N,N-dimethylformamide (50 ml),followed by addition of p-toluenesulfonic acid·monohydrate (941 mg), andstirred at 120° C. for 59 hours. After the reaction solution was cooledto ambient temperature, the resulting solution was concentrated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (eluent: chloroform-chloroform/methanol=100/1 to50/1 to 20/1), to afford3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole as paleyellow solid (5.98g, 68%). A part of the product was recrystallized fromethyl acetate, to afford the entitled compound as pale yellow crystal.The physico-chemical values are as follows.

mp: 201–204° C. ¹H-NMR (DMSO-d₆) δ: 1.15 (3H, d, J=6.8 Hz), 1.28 (3H, d,J=6.8 Hz), 2.72–2.82 (1H, m), 7.36–7.54 (7H, m), 7.66–7.71 (5H, m), 7.83(1H, ddd, J=1.4 Hz, 7.8 Hz, 7.8 Hz).

Reference Example 2 N-(2-Bromophenyl)-6-phenylthionicotinimidate ethylester

-   (1) 6-Phenylnicotinic acid (10.1 g) was dissolved in    dimethylformamide (100 ml), followed by addition of    1-hydroxybenzotriazole (7.54 g),    1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride    salt(10.7 g) and 2-bromoaniline (8.72 g), and stirred at ambient    temperature for 13 hours, at 60° C. for 4 hours and at 100° C. for 2    hours. After the reaction solution was cooled to ambient    temperature, the resulting solution was concentrated under reduced    pressure, followed by addition of water and chloroform. The organic    layer was separated, washed sequentially in water, saturated aqueous    sodium hydrogen carbonate solution and water, and dried over    anhydrous magnesium sulfate. After the solvent was evaporated under    reduced pressure, the resulting residue was washed with a mixture    solvent of n-hexane and diisopropyl ether, to afford    N-(2-bromophenyl)-6-phenylnicotinamide as white solid (11.3 g, 63%).    The physico-chemical values are as follows.

¹H-NMR (DMSO-d₆) δ: 7.23–7.31 (1H, m), 7.42–7.63 (5H, m), 7.75 (1H, dd,J=1.0, 7.8 Hz), 8.13–8.23 (3H, m), 8.42 (1H, dd, J=2.4, 8.3 Hz), 9.24(1H, dd, J=2.0 Hz), 10.32 (1H, s).

-   (2) N-(2-Bromophenyl)-6-phenylnicotinamide (11.3 g) was dissolved in    toluene (200 ml), followed by addition of the Lawesson reagent (7.12    g), and refluxed under heating for 3 hours. The resulting residue    was purified by silica gel column chromatography (eluent:    toluene-toluene/acetone=20/1), to afford an oily product.    Subsequently, the oily product was dissolved in ethanol (70 ml),    followed by addition of aqueous 0.5 mol/liter sodium hydroxide    solution (130 ml) and methyl iodide(3.0 ml), and stirred at ambient    temperature for 2 hours. After ethyl acetate was added to the    reaction solution to separate the organic layer, the organic layer    was washed with saturated aqueous sodium chloride and dried over    anhydrous magnesium sulfate. After the solvent was evaporated under    reduced pressure, the resulting residue was purified by silica gel    column chromatography (developing solvent: n-hexane/ethyl    acetate=10/1), to affordr the entitled compound    N-(2-bromophenyl)-6-phenylthionicotinimidate methyl ester as yellow    oil (8.46 g, 69%). The physico-chemical values are as follows.

¹H-NMR (DMSO-d₆) δ: 2.85 (3H, brs), 6.60–8.20 (11H, m), 8.52 (1H, brs).

Production Example 25-[4-(2-Bromophenyl)-4H-1,2,4-triazol-3-yl]-2-phenylpyridine

N-(2-Bromophenyl)-6-phenylthionicotinimidate methyl ester (8.46 g)prepared in the Reference Example 2 was dissolved inN,N-dimethylformamide (20 ml), followed by addition of formyl hydrazide(2.65 g) and p-toluenesulfonic acid·monohydrate (420 mg), and stirred at140° C. for 23 hours. After the reaction solution was cooled to ambienttemperature, saturated aqueous sodium hydrogen carbonate solution wasadded to the resulting solution, and extracted with chloroform. Theextract was dried over anhydrous magnesium sulfate. After the solventwas evaporated under reduced pressure, the resulting residue waspurified by silica gel column chromatography (eluent:chloroform/methanol=100/1), to afford the entitled compound as yellowsolid (8.34 g, quantitative). The physico-chemical values are asfollows.

FAB-MS m/z: 377 (M⁺+H). ¹H-NMR (DMSO-d₆) δ: 7.30–7.69 (5H, m), 7.79–7.91(3H, m), 8.00–8.12 (3H, m), 8.66 (1H, brd, J=2.1 Hz), 8.96 (1H, s).

Production Example 35-[5-Bromo-4-(2-bromophenyl)-4H-1,2,4-triazol-3-yl]-2-phenylpyridine

5-[4-(2-Bromophenyl)-4H-1,2,4-triazol-3-yl]-2-phenylpyridine prepared inthe Production Example 2 was dissolved in a mixture solvent of carbontetrachloride (100 ml) and acetic acid (100 ml), followed by addition ofn-bromosuccinimide (5.90 g), and refluxed under heating for 3 hours.After the reaction solution was cooled to ambient temperature, thesolution was concentrated-under reduced pressure. Saturated aqueoussodium hydrogen carbonate solution was added to the resulting residue,and extracted with chloroform. Subsequently, the organic layer was driedover anhydrous magnesium sulfate. After the solvent was evaporated underreduced pressure, the resulting residue was purified by silica gelcolumn chromatography (eluent: n-hexane/ethyl acetate=3/1), to affordthe entitled compound as yellow solid (6.96 g, 69%). Thephysico-chemical values are as follows.

FAB-MS m/z: 454 (M⁺+H). ¹H-NMR (DMSO-d₆) δ: 7.43–7.52 (3H, m), 7.62 (1H,ddd, J=2.0, 7.8, 7.8 Hz), 7.71 (1H, ddd, J=1.5, 7.8, 7.8 Hz), 7.83 (1H,dd, J=2.5, 8.3 Hz), 7.92–7.98 (2H, m), 8.05 (1H, dd, J=1.0, 8.3 Hz),8.06–8.11 (2H, m), 8.67 (1H, dd, J=1.0, 2.5 Hz).

Reference Example 3N-(2,1,3-Benzooxadiazol-4-yl)-6-phenylthionicotinimidate methyl ester

In the same manner as in the Reference Example 1, the entitled compoundas yellow oil was obtained from 2,1,3-benzooxadiazol-4-ylamine and6-phenylnicotinoyl chloride. The physico-chemical values are as follows.

¹H-NMR (CDCl₃) δ: 2.60 (3H, s), 6.53–6.55 (1H, m), 7.20–7.96 (9H, m),8.65–8.72 (1H, m).

Production Example 44-[3-(6-Phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzooxadiazole

In the same manner as in the Production Example 2, the entitled compoundas yellow solid was obtained (2.80 g, 96%) fromN-(2,1,3-benzooxadiazol-4-yl)-6-phenylthionicotinimidate methyl ester(2.96 g) prepared in the Reference Example 3. The physico-chemicalvalues are as follows.

FAB-MS m/z: 341 (M⁺+H). ¹H-NMR (DMSO-d₆) δ: 7.45–7.53 (3H, m), 7.78 (1H,m), 7.88 (1H, d, J=7.0 Hz), 7.91–8.05 (4H, m), 8.26 (1H, d, J=9.0 Hz),8.81 (1H, m), 9.15 (1H, s).

Production Example 54-[3-Bromo-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzooxadiazole

In the same manner as in the Production Example 3, the entitled compoundas yellow solid was obtained (1.01 g, 46%) from4-[3-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzooxadiazole(1.80 g) recovered in the Production Example 4. The physico-chemicalvalues are as follows.

FAB-MS m/z: 419 (M⁺+H). ¹H-NMR (DMSO-d₆) δ: 7.45–7.53 (3H, m), 7.85–7.91(2H, m), 7.95 (1H, d, J=8.3 Hz), 8.03–8.08 (2H, m), 8.18 (1H, d, J=6.9Hz), 8.41 (1H, d, J=9.3 Hz), 8.76 (1H, d, J=1.9 Hz).

In the same manner, compounds shown in Table (1) were syntheticallyprepared.

In the table, the abbreviations represent the following.

-   Pr.Ex.: Production Example No.-   Ph: phenyl-   Pyr: pyridyl-   Me: methyl-   Et: ethyl-   iPr: isopropyl-   cPr: cyclopropyl-   cHex: cyclohexyl-   Ac: acetyl-   Bz: benzoyl-   Py: pyridyl-   Qin: quinolyl-   Im: imidazolyl.

Herein, the substituting position of a substituent capable ofsubstituting plural positions is expressed before the substituent (ex.6-Br). Additionally, the binding position of hetero ring is expressedbefore the hetero ring (ex. 4-Py, 2-Qin).

(1)

Ring Substituent on Ring Substituent on Substituent PrEx. Ra A UZ,13/24ring A B ring B Ring D on ring D DATA: MS m/z 6 Me Ph 2-OMe Ph H2-thiophen H M⁺ + H: 348 (ESI) 7 Me Ph 2-OMe Ph H 2-benzofuran H M⁺ + H:382 (ESI) 8 Me Ph 2-F — Ph H Ph H M⁺ + H: 330 (FAB) 9 Et Ph 2-F — Ph HPh H M⁺ + H: 344 (FAB) 10 Me Ph 2-NH₂ — Ph H Ph H M⁺ + H: 327 (FAB) 11Me Ph 1H-Im-1-y1 — Ph H Ph H M⁺ + H: 378 (FAB) 12 Me(CH₂)₂— Ph 2-F — PhH Ph H M⁺+ H: 358 (FAB) 13 Me(CH₂)₃— Ph 2-F — Ph H Ph H M⁺+ H: 372 (FAB)14 Me(CH₂)₄— Ph 2-F — Ph H Ph H M⁺+ H: 386 (FAB) 15 Me(CH₂)₅— Ph 2-F —Ph H Ph H M⁺+ H: 400 (FAB) 16 Me₂CHCH₂— Ph 2-F — Ph H Ph H M⁺+ H: 372(FAB) 17 Me Ph 2-OMe 6-Me Ph H Ph H M⁺ + H: 356 (FAB) 18 Me Ph 5-NO₂2-OMe Ph H Ph H M⁺ + H: 387 (FAB) 19 Me Ph 5-CF3 2-OMe Ph H Ph H M⁺ + H:410 (FAB) 20 Me Ph 4-F — Ph H Ph H M⁺ + H: 330 (FAB) 21 Et Ph 2-F 6-F PhH Ph H M⁺ + H: 362 (FAB) 22 Et Ph 2-F 3-F Ph H Ph H M⁺ + H: 362 (FAB) 23Et Ph 2-Cl 6-Cl Ph H Ph H M⁺ + H: 394 (FAB) 24 Et Ph 2-Cl 3-Cl Ph H Ph HM⁺ + H: 394 (FAB) 25 Et Ph 2-Me — Ph H Ph H M⁺ + H: 340 (FAB) 26 Me Ph2-NHMe — Ph H Ph H M⁺ + H: 341 (FAB) 27 Me Ph 2-OMe — Ph H Ph 3,5-di-ClM⁺ : 410 (ESI) 28 Me₂CH— Ph H — Ph H Ph H M⁺ + H: 340 (FAB) 29 Me₃C— Ph2-F — Ph H Ph H M⁺ + H: 372 (FAB) 30 Br— Ph 2-F — Ph H Ph H M⁺ + H: 395(FAB) 31 Me Ph 2-Et — Ph H Ph H M⁺ + H: 340 (FAB) 32 Me Ph 2-Me(CH₂) —Ph H Ph H M⁺ + H: 354 (FAB) 33 Et Ph 2-OH — Ph H Ph H M⁺ + H: 342 (FAB)34 Me Ph 2-F — Ph H Ph 3,5-di-CF₃ M⁺ + H: 466 (FAB) 35 Me Ph 3-F — Ph HPh H M⁺ + H: 330 (FAB) 36 Me Ph 3-CF₃ — Ph H Ph 3,5-di-CF₃ M⁺ + H: 516(FAB) 37 Et Ph 3-CF₃ 2-F Ph H Ph H M⁺ + H: 412 (FAB) 38 Et Ph 2-Me 3-CF₃Ph H Ph H M⁺ + H: 408 (FAB) 39 Et Ph 2-Me 3-Me Ph H Ph H M⁺ + H: 354(FAB) 40 Et Ph 2-Me 3-F Ph H Ph H M⁺ + H: 358 (FAB) 41 Et Ph 2-Me 3-ClPh H Ph H M⁺ + H: 374 (FAB) 42 Et Ph 2-Me 3-Br Ph H Ph H M⁺ + H: 418(FAB) 43 Et Ph 2-Me 3-NH₂ Ph H Ph H M⁺ + H: 355 (FAB) 44 Et Ph 2-Me3-NMe₂ Ph H Ph H M⁺ + H: 383 (FAB) 45 Et Ph 2-Me 3-OH Ph H Ph H M⁺ + H:356 (FAB) 46 Et Ph 2-Me 3-OMe Ph H Ph H M⁺ + H: 370 (FAB) 47 Et Ph 2-Me3-Cn Ph H Ph H M⁺ + H: 365 (FAB) 48 Et Ph 3-C≡CH 2-Me Ph H Ph H M⁺ + H:364 (FAB) 49 Et Ph 2-Me 3-NO₂ Ph H Ph H M⁺ + H: 385 (FAB) 50 Et Ph 2-Cl3-CN Ph H Ph H M⁺ + H: 385 (FAB) 51 Et Ph 2-F 3-CN Ph H Ph H M⁺ + H: 369(FAB) 52 Et Ph 2-OH 3-CN Ph H Ph H M⁺ + H: 367 (FAB) 53 Et- Ph 2-F — Ph2-Cl Ph H M⁺ + H: 378 (FAB) 54 Et- Ph 2-F — Ph 3-Cl Ph H M⁺ + H: 378(FAB)

Reference Example 4 N-(2,6-Difluorophenyl)-2-methylthiopropionimidatemethyl ester

In the same manner as in the Reference Example 1, the entitled compoundas colorless oil was obtained from 2,6-difluoroaniline. Thephysico-chemical values are as follows.

FAB-MS m/z: 230 (M⁺+H).

Example 15-[4-(2,6-Difluorophenyl)-5-isopropyl-4H-triazol-3-yl]-2-phenylpyridine

In the same manner as in the Production Example 1, the entitled compoundas white crystal (recrystallized from ethyl acetate) was obtained (467mg, 35%) from N-(2,6-difluorophenyl)-2-methylthiopropionimidate methylester (2.32 g) prepared in the Reference Example 4 and 6-phenylnicitinicacid hydrazide (750 mg). The physico-chemical values are as follows.

mp: 183–185° C. ¹H-NMR (DMSO-d₆) δ: 1.24 (6H, d, J=8 Hz), 2.76–2.85 (1H,m), 7.44–7.56 (5H, m), 7.76–7.85 (2H, m), 8.05 (1H, dd, J=8.3 Hz),8.06–8.12 (2H, m), 8.64 (1H, d, J=1.9 Hz).

Reference Example 5N-(2,1,3-Benzooxodiazol-4-yl)-2-methylthiopropionimidate methyl ester

In the same manner as in the Reference Example 1, the entitled compoundwas obtained as yellow oil from 2,1,3-benzooxadiazol-4-ylamine. Thephysico-chemical values are as follows.

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.8 Hz), 2.91 (1H, m), 6.56 (1H, dd,J=0.6, 6.8 Hz), 7.35 (1H, dd, J=9.2, 6.9 Hz), 7.47 (1H, dd, J=0.7, 9.0Hz).

Example 2 4-[3-Isopropyl5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzooxadiazole

In the same manner as in the Production Example 1, the entitled compoundas white crystal (recrystallized from a mixture solvent of n-hexane andtoluene) was obtained (126 mg, 22%) fromN-(2,1,3-benzooxadiazol-4-yl)-2-methylthiopropionimidate methyl ester(323 mg) prepared in the Reference Example 5 and 6-phenylnicotinic acidhydrazide (500 mg). The physico-chemical values are as follows.

mp: 107–108° C. ¹H-NMR (DMSO-d₆) δ: 1.12 (3H, d, J=6.9 Hz), 1.29 (3H, d,J=6.9 Hz), 2.86–2.98 (1H, m), 7.40–7.50 (3H, m), 7.78–7.86 (2H, m), 7.91(1H, d, J=8.3 Hz), 8.01–8.05 (2H, m), 8.12 (1H, d, J=6.8 Hz), 8.34 (1H,d, J=8.8 Hz), 8.69 (1H, d, J=2.0 Hz).

Example 3 5-(3-Biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline

A mixture of 2-biphenyl-4-yl-5-ethyl-1,3,4-oxodiazole (3.00 g),5-aminoisoquinoline (3.00 g) and p-toluenesulfonic acid·monohydrate(0.65 g) was stirred at 150° C. for 3 hours, followed by addition ofp-toluenesulfonic acid-monohydrate (0.65 g), and further stirred at 180°C. for 6 hours. The reaction mixture was cooled to ambient temperature,followed by addition of water and chloroform. Subsequently, potassiumcarbonate was added to the mixture, to adjust the mixture to basic.After the organic layer was separated, the aqueous layer was extractedwith chloroform. The organic layers were combined together, washed withsaturated aqueous sodium chloride, and dried over anhydrous magnesiumsulfate. After the solvent was evaporated under reduced pressure, theresulting residue was purified by alumina column chromatography (eluent:chloroform) and subsequently by silica gel column chromatography(eluent: chloroform/methanol=20/1), and was then recrystallized fromethyl acetate, to afford the entitled compound as colorless needlecrystal (1.45 g, 32%). The physico-chemical values are as follows.

mp: 228–230° C. ¹H-NMR (CDCl₃) δ: 1.09 (3H, t, J=7.6 Hz), 2.33–2.50 (2H,m), 7.11 (1H, d, J=5.8 Hz), 7.31–7.42 (5H, m), 7.53–7.58 (4H, m),7.89–7.91 (1H, t, J=7.9 Hz), 8.17 (1H, d, J=7.4 Hz), 8.42 (1H, d, J=8.3Hz), 8.54 (1H, d, J=6.3 Hz), 9.51 (1H, s).

Reference Example 6 3-Amino-2-methylbenzamide

2-Methyl-3-nitrobenzamide (8.85 g) was dissolved in a mixture solvent ofethanol (300 ml) and tetrahydrofuran (200 ml), followed by addition of10% palladium-carbon (800 mg). The resulting mixture was stirred underhydrogen atmosphere at ambient temperature and atmospheric pressure for6 hours. After insoluble materials were filtered off, the filtrate wasconcentrated under reduced pressure and washed with isopropyl ether, toafford the entitled compound as white solid (6.73 g, 91%). Thephysico-chemical values are as follows.

¹H-NMR (DMSO-d₆) δ: 2.04 (3H, s), 4.91(2H, s), 6.51 (1H, dd J=1.0 Hz,7.5 Hz), 6.64 (1H, dd, J=1.0 Hz, 7.5 Hz), 6.88 (1H, dd, J=7.0 Hz, 7.5Hz), 7.18 (1H, s), 7.51 (1H, s).

Reference Example 75-[5-(3-Methoxypropyl)-1,3,4-oxadiazol-2-yl]-2-phenylpyridine

(1) Carbazic acid tert-butyl ester (9.21 g) was dissolved in pyridine(120 ml), followed by addition of 4-methoxybutyric acid (9.06 g) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (20.0g), and stirred at ambient temperature for 64 hours. After the reactionsolution was concentrated under reduced pressure, ethyl acetate wasadded to the residue, which was then washed with aqueous 1 mol/literhydrochloric acid solution, saturated aqueous sodium hydrogen carbonatesolution and saturated aqueous sodium chloride, and dried over anhydroussodium sulfate. After the solvent was evaporated under reduced pressure,N′-(4-methoxybutyryl)hydrazine carboxylic acid tert-butyl ester wasobtained in yellow oil (9.30 g, 57%). The physico-chemical values are asfollows.

¹H-NMR (DMSO-d₆) δ: 1.39 (9H, s), 1.65–1.78 (2H, m), 2.07–2.12 (2H, m),3.21 (3H, s), 3.30–3.34 (2H, m), 8.64 (1H, s), 9.46 (1H, s).

(2) N′-(4-Methoxybutyryl)hydrazine carboxylic acd tert-butyl ester (9.30g) was dissolved in ethyl acetate (50 ml), followed by addition of 4mol/liter hydrochloric acid/ethyl acetate solution (150 ml), and stirredat ambient temperature for 2 hours. After the reaction solution wasconcentrated under reduced pressure, the resulting residue was washedwith n-hexane, to afford 4-methoxybutyric acid hydrazide hydrochloridesalt as pale yellow solid (5.99 g, 89%). The physico-chemical values areas follows.

¹H-NMR (DMSO-d₆) δ: 1.71–1.80 (2H, m), 2.27 (2H, t, J=7.5 Hz), 3.22 (3H,s), 3.31 (2H, t, J=6.3 Hz), 10.43 (3H, brs), 11.04 (1H, s).

(3) 6-Phenylnicotinic acid (5.90 g) was dissolved in pyridine (150 ml),followed by addition of 4-methoxybutyric acid hydrazide hydrochloridesalt (5.99 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride salt (8.51 g), and stirred at 60° C. for 10 hours. Afterthe reaction solution was cooled to ambient temperature, the solvent wasevaporated under reduced pressure. The resulting residue was washed withwater, to afford 6-phenylnicotinic acid N′-(4-methoxybutyryl)hydrazideas pale yellow solid (6.06 g, 65%). The physico-chemical values are asfollows.

¹H-NMR (DMSO-d₆) δ: 1.75–1.84 (2H, m), 2.26 (2H, t, J=7.4 Hz), 3.25 (3H,s), 3.37 (2H, t, J=6.4 Hz), 7.43–7.57 (3H, m), 8.11–8.19 (3H, m), 8.31(1H, dd, J=2.7 Hz, 8.3 Hz), 9.10–9.12 (1H, m), 9.96 (1H, brs), 10.53(1H, brs).

(4) To 6-phenylnicotinic acid N′-(4-methoxybutyryl)hydrazide (6.06 g)was added phosphorus oxychloride (100 ml), and stirred at 100° C. for 3hours. After the reaction solution was cooled to ambient temperature,the solution was concentrated under reduced pressure. To the resultingresidue was added aqueous 1 mol/liter sodium hydroxide solution underice cooling, and extracted with chloroform. After the organic layer wasdried over anhydrous sodium sulfate, the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: n-hexane/ethyl acetate=3/1 to 1/1 to 1/2 to1/5), and washed with a mixture solvent of n-hexane and ethyl acetate,to afford the entitled compound5-[5-(3-methoxypropyl)-1,3,4-oxadiazol-2-yl]-2-phenylpyridine 3.72 g,65%). The physico-chemicalvalues are as follows.

¹H-NMR (DMSO-d₆) δ: 2.01–2.10 (2H, m), 3.02 (2H, t, J=7.4 Hz), 3.28 (3H,s), 3.47 (2H, t, J=6.0 Hz), 7.46–7.56 (3H, m), 8.13–8.22 (3H, m), 8.40(1H, dd, J=2.2 Hz, 8.4 Hz), 9.22–9.23 (1H, m).

Example 43-[3-(3-Methoxypropyl)-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzamide

5-[5-(3-Methoxypropyl)-1,3,4-oxadiazol-2-yl]-2-phenylpyridine (1.0 g)prepared in the Reference Example 7 was dissolved in1,3-dimethyl-2-imidazolidinone (10 ml), followed by addition of3-amino-2-methylbenzamide (1.53 g) prepared in the Reference Example 6and D-10-camphorsulfonic acid (290 mg), and stirred at 200° C. for 16hours. After the reaction solution was cooled to ambient temperature,chloroform was added to the solution, which was then washed withsaturated aqueous sodium hydrogen carbonate solution. The organic layerwas dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The resulting residue was purified bysilica gel column chromatography (eluent: chloroform/methanol=10/1), toafford the entitled compound (812 mg, 56%). The physico-chemical valuesare as follows.

FAB-MS m/z: 428 (M⁺+H). ¹H-NMR (DMSO-d₆) δ: 1.86–1.93 (2H, m), 1.89 (3H,s), 2.46–2.54 (2H, m), 3.17 (3H, s), 3.34–3.37 (2H, m), 7.43–7.53 (4H,m), 7.58–7.62 (2H, m), 7.67 (1H, brd, J=7.3 Hz), 7.83 (1H, dd, J=2.4 Hz,8.3 Hz), 7.96–8.00 (2H, m), 8.06–8.09 (2H, m), 8.60 (1H, d, J=2.4 Hz).

Example 53-[3-(3-Methoxypropyl)-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile

Phosphorus oxychloride (8 ml) was added to3-[3-(3-methoxypropyl)-5-(6-phenylpyridin-3-yl)-1,2,4-triazol-4-yl]-2-methylbenzamide(770 mg) prepared in the Example 4, and refluxed under heating for 3hours. After the reaction solution was cooled to ambient temperature,the solution was concentrated under reduced pressure. Chloroform wasadded to the resulting residue, which was then washed with saturatedaqueous sodium hydrogen carbonate solution. Subsequently, the organiclayer was dried over anhydrous magnesium sulfate. After the solvent wasevaporated under reduced pressure, the resulting solid wasrecrystallized from ethyl acetate, to afford the entitled compound aswhite crystal (386 mg, 52%). The physico-chemical values are as follows.

mp: 144–145° C. ¹H-NMR (DMSO-d₆) δ: 1.84–1.92 (2H, m), 2.08 (3H, s),2.45–2.61 (2H, m), 3.17 (3H, s), 3.35 (2H, t, J=6.4 Hz), 7.43–7.52 (3H,m), 7.68 (1H, t, J=7.8 Hz), 7.77 (1H, dd, J=8.3, 1.9 Hz), 7.97–8.02 (2H,m), 8.06–8.12 (3H, m), 8.64 (1H, d, J=2.5 Hz).

Reference Example 8 5-(5-Ethyl-1,3,4-oxadiazol-2-yl)-2-phenylpyridine

In the same manner as in the Reference Example 7, the entitled compoundwas obtained as pale yellow solid from propionic acid. Thephysico-chemical values are as follows.

¹H-NMR (DMSO-d₆) δ: 1.37 (3H, t, J=7.6 Hz), 2.99 (2H, q, J=7.6 Hz),7.43–7.58 (3H, m), 8.16–8.21 (3H, m), 8.41 (1H, dd, J=2.2 Hz, 8.4 Hz),9.22–9.24 (1H, m).

Example 63-[3-Ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile

In the same manner as in Example 4,3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzamideas yellow solid (550 mg, 57%) was obtained from5-ethyl-1,3,4-oxadiazol-2-yl)-2-phenylpyridine (630 mg) prepared in theReference Example 8 and 3-amino-2-methylbenzamide (1.13 g) prepared inthe Reference Example 6.

Subsequently, the entitled compound as white crystal was obtained (242mg, 46%) from3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzamide(550 mg). The physico-chemical values are as follows.

mp: 162–163° C. ¹H-NMR (DMSO-d₆) δ: 1.19 (3H, t, J=7.5 Hz), 2.08 (3H,s), 2.41–2.59 (2H, m), 7.43–7.52 (3H, m), 7.67 (1H, dd, J=7.8, 8.3 Hz),7.76 (1H, dd, J=2.5, 8.3 Hz), 7.98–8.02 (2H, m), 8.05–8.12 (3H, m), 8.64(1H, d, J=2.5 Hz).

Example 7[4-(2-Bromophenyl)-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]-N-(2-methoxyethyl)-N-methylamine

In a sealed tube, N-(2-methoxyethyl)methylamine (3 ml) was added to5-[5-bromo-4-(2-bromophenyl)-4H-1,2,4-triazol-3-yl]-2-phenylpyridine(1.0 g) prepared in the Production Example 3, and stirred at 180° C. for13 hours and at 200° C. for 24 hours. After the reaction solution wascooled to ambient temperature, chloroform was added to the solution,which was then washed with saturated aqueous sodium hydrogen carbonatesolution. The organic layer was dried over anhydrous magnesium sulfate.After the solvent was evaporated under reduced pressure, the resultingresidue was washed with ethyl acetate, to afford the entitled compoundas white solid (711 mg, 70%). The physico-chemical values are asfollows.

FAB-MS m/z: 464 (M⁺+H). ¹H-NMR (DMSO-d₆) δ: 2.77 (3H, s), 3.15 (3H, s),3.15–3.31 (4H, m), 7.43–7.52 (4H, m), 7.65 (1H, t, J=7.8 Hz), 7.73 (1H,dd, J=2.0, 8.3 Hz), 7.85 (1H, d, J=8.3 Hz), 7.96–7.98 (2H, m), 8.04–8.07(2H, m), 8.56 (1H, d, J=2.4 Hz).

Example 82-{3-[N-(2-Methoxyethyl)-N-methylamino]-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl}benzonitrile

[4-(2-Bromophenyl)-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]-N-(2-methoxyethyl)-N-methylamine(436 mg) prepared in the Example 7 was dissolved inN-methyl-2-pyrrolidone (5 ml), followed by addition of zinc cyanide (121mg), calcium hydroxide (76 mg) and tetrakistriphenylphosphine palladium(326 mg), and stirred at 180° C. for 3 hours. After the reactionsolution was cooled to ambient temperature, chloroform was added to thesolution, from which insoluble materials were filtered off. The filtratewas washed with saturated aqueous sodium hydrogen carbonate solution,and the organic layer was dried over anhydrous magnesium sulfate. Afterthe solvent was evaporated under reduced pressure, the resulting solidwas recrystallized from ethyl acetate, to afford the entitled compoundas white crystal (242 mg, 63%). The physico-chemical values are asfollows.

mp: 148–149° C. ¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 3.11 (2H, t, J=5.8Hz), 3.14 (3H, s), 3.25–3.33 (2H, m), 7.43–7.52 (3H, m), 7.72 (1H, dd,J=2.5 Hz, 8.8 Hz), 7.79 (1H, dt, J=1.0 Hz, 7.8 Hz), 7.96–8.02 (2H, m),8.04–8.12 (4H, m), 8.56 (1H, d, J=2.0 Hz).

Example 94-(2,1,3-Benzooxadiazol-4-yl)-N-(2-methoxyethyl)-N-methyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-3-ylamine

In a sealed tube, N-(2-methoxyethyl)methylamine (3 ml) and water (3 ml)were added to4-[3-bromo-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzooxadiazol(336 mg) prepared in the Production Example 5, and stirred at 160° C.for 6 hours. After the reaction solution was cooled to ambienttemperature, chloroform was added to the solution, which was then washedwith saturated aqueous sodium hydrogen carbonate solution. The organiclayer was dried over anhydrous magnesium sulfate. After the solvent wasevaporated under reduced pressure, the resulting solid wasrecrystallized from ethyl acetate, to afford the entitled compound aswhite crystal (66 mg, 19%). The physico-chemical values are as follows.

mp: 133–134° C. ¹H-NMR (DMSO-d₆) δ: 2.76 (3H, s), 3.00 (3H, s),3.05–3.25 (4H, m), 7.40–7.50 (3H, m), 7.75–7.82 (2H, m), 7.90 (1H, d,J=8.8 Hz), 8.00–8.10 (3H, m), 8.30 (1H, d, J=9.3 Hz), 8.67 (1H, d, J=2.5Hz).

Reference Example 9 N-(2-Fluorophenyl)thioacetoimidate methyl ester

In the same manner as in the Reference Example 1, the entitled compoundwas obtained in pale yellow oil from 2-fluoroaniline. Thephysico-chemical values are as follows.

¹H-NMR (CDCl₃) δ: 1.59 (3H, brs), 2.02 (3H, brs), 6.78–6.85 (1H, m),6.98–7.11 (3H, m).

Reference Example 103-(4-Bromophenyl)-4-(2-fluorophenyl)-5-methyl-4H-1,2,4-triazole

In the same manner as in the Production Example 1, the entitled compoundwas obtained as white solid (810 mg, 89%) fromN-(2-fluorophenyl)thioacetoimidate methyl ester (500 mg) prepared in theReference Example 9 and 4-bromobezoic acid hydrazide (705 mg). Thephysico-chemical values are as follows.

FAB-MS m/z: 332 (M⁺+H). ¹H-NMR (DMSO-d₆) δ: 2.25 (3H, s), 7.28–7.75 (8H,m).

Example 104-(2-Fluorophenyl)-3-methyl-5-(4-thiophen-2-ylphenyl)-4H-1,2,4-triazole

3-(4-Bromophenyl)-4-(2-fluorophenyl)-5-methyl-4H-1,2,4-triazole (150 mg)prepared in the Reference Example 10 was dissolved in1,2-dimethoxyethane (2 ml), followed by addition oftetrakis(triphenylphosphine)palladium (26 mg), and stirred at ambienttemperature for 15 minutes. Subsequently, a solution of 2-thiophenboricacid (150 mg) in ethanol (0.5 ml) and aqueous 2 mol/liter sodiumcarbonate solution (0.45 ml) were added to the resulting mixture, andrefluxed under heating for 4 hours. After the reaction solution wascooled to ambient temperature, insoluble materials were filtered off. Tothe resulting filtrate was added saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The resulting residue was purified bysilica gel chromatography (eluent: chloroform/methanol=99/1 to 97/3) andrecrystallized from ethanol, to afford the entitled compound as whitesolid (100 mg, 66%). The physico-chemical values are as follows.

FAB-MS m/z: 336 (M⁺+H). ¹H-NMR (DMSO-d₆) δ: 2.24 (3H, s), 7.12 (1H, dd,J=3.5, 4.5 Hz), 7.38–7.68 (10H, m).

Example 113-{4-[4-(2-Fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]phenyl}pyridine

3-(4-Bromophenyl)-4-(2-fluorophenyl)-5-methyl-4H-1,2,4-triazole (500 mg)prepared in the Reference Example 10 was dissolved in tetrahydrofuran(15 ml), followed by addition of n-butyl lithium (1.57 mol/liter hexanesolution; 1.2 ml) at −78° C., and stirred at the same temperature for 20minutes. Borate methyl ester (0.50 ml) was added to the mixture andstirred at ambient temperature for 3 hours. Under ice cooling, aqueous 2mol/liter hydrochloric acid solution was added to adjust the solution toabout pH 4, followed by extraction with chloroform. The organic layerwas washed with saturated aqueous saline. The organic layer was driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure, to afford a borate derivative as pale yellow oil (660mg).

3-Bromopyridine (0.15 ml) was dissolved in 1,2-dimethoxyethane (5 ml),followed by addition of tetrakis(triphenylphosphine)palladium (87 mg),and stirred at ambient temperature for 15 minutes. To the reactionsolution were added a solution of the borate derivative in ethanol (2ml) and aqueous 2 mol/liter sodium carbonate solution (1.5 ml), andrefluxed heating for 3 hours. After the reaction solution was cooled toambient temperature, insoluble materials were filtered off, and thesolvent was evaporated under reduced pressure. The resulting residue waspurified by silica gel chromatography (eluent: chloroform/methanol=98/2)and washed with a mixture solvent of n-hexane and ethyl acetate, toafford the entitled compound as white solid (140 mg, 28%). Thephysico-chemical values are as follows.

FAB-MS m/z: 331 (M⁺+H). ¹H-NMR (DMSO-d₆) δ: 2.26 (3H, s), 7.44–7.56 (5H,m), 7.63–7.70 (1H, m), 7.74–7.79 (3H, m), 8.07–8.11 (1H, m), 8.56–8.60(1H, m), 8.88–8.92 (1H, m).

Example 123-Biphenyl-4-yl-4-(2-fluorophenyl)-5-methylsulfanyl-4H-1,2,4-triazole

(1)Biphenyl-4-carboxylic acid hydrazide (10.0 g) was dissolved inethanol (250 ml), followed by addition of 2-fluorophenylisothiocyanate(5.8 ml), and stirred ambient temperature for 2 hours. The precipitatewas filtered, to afford1-(biphenyl-4-carbonyl)-4-(2-fluorophenyl)-thiosemicarbazide as whitesolid (12.3 g, 72%). The physico-chemical values are as follows.

FAB-MS m/z: 366 (M⁺+H). ¹H-NMR (DMSO-d₆) δ: 7.15–7.45 (5H, m), 7.50 (2H,t, J=7.5 Hz), 7.75 (2H, d, J=7.5 Hz), 7.82 (2H, d, J=8.5 Hz), 8.05 (2H,d, J=8.5 Hz), 9.64 (1H, s), 9.89 (1H, s), 10.66 (1H, s).

(2) 1-(Biphenyl-4-carbonyl)-4-(2-fluorophenyl)thiosemicarbazide (12.1 g)was suspended in aqueous 2 mol/liter sodium hydroxide solution (300 ml),and refluxed under heating for 3 hours. After the reaction solution wascooled to ambient temperature, the solution was neutralized under icecooling with conc. hydrochloric acid. The precipitate was filtered andwashed with water, to afford5-biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazole-3-thiol as paleyellow solid (11.2 g, 97%). The physico-chemical values are as follows.

FAB-MS m/z: 348 (M⁺+H). ¹H-NMR (DMSO-d₆) δ: 7.33–7.52 (8H, m), 7.53–7.70(6H, m).

(3) 5-Biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazole-3-thiol (2.7 g)was dissolved in acetonitrile (50 ml), followed by addition of methyliodide (0.967 ml) and potassium carbonate (1.07 g), and stirred atambient temperature for 3 hours. Water was added to the reactionsolution, followed by extraction with chloroform. The organic layer waswashed with saturated aqueous saline and dried over anhydrous magnesiumsulfate. After the solvent was evaporated under reduced pressure, theresulting solid was recrystallized from a mixture solvent ofacetonitrile and ethyl acetate, to afford the entitled compound3-biphenyl-4-yl-4-(2-fluorophenyl)-5-methylsulfanyl-4H-1,2,4-triazole aspale yellow crystal (2.03 g, 72%). The physico-chemical values are asfollows.

mp: 199–200° C. ¹H-NMR (DMSO-d₆) δ: 2.65 (3H, s), 7.35–7.56 (7H, m),7.65–7.72 (5H, m), 7.77 (1H, dt, J=2.0, 7.8 Hz).

Example 133-Benzyloxymethyl-5-biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazole

(1) Biphenyl-4-carboxylic acid hydrazide (6.4 g) was dissolved inN,N-dimethylformamide (50 ml), followed by sequential addition oftetrahydrofuran (100 ml), benzyloxyacetic acid (5.0 g),1-hydroxybenzotriazole (0.30 g) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (6.3g), and stirred at ambient temperature for 2 hours. After the reactionsolution was concentrated under reduced pressure, water was added to theresulting residue, and the precipitate was filtered. The precipitate wassequentially washed with aqueous 0.15 mol/liter hydrochloric acidsolution and water, to afford biphenyl-4-carboxylic acidN′-(2-benzyloxyacetyl)hydrazide as pale yellow solid (10.8 g,quantitative). The physico-chemical values are as follows.

FAB-MS m/z: 361.

(2) To biphenyl-4-carboxylic acid N′-(2-benzyloxyacetyl)hydrazide (9.38g) was added phosphorus oxychloride (30 ml), and stirred at 100° C. forone hour. After the reaction solution was cooled to ambient temperature,the reaction solution was concentrated under reduced pressure. To theresulting residue was added ethyl acetate, and the separated organiclayer was washed with aqueous 1 mol/liter sodium hydroxide solution anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure to afford an oily product. Subsequently,2-fluoroaniline (5 ml) and p-toluenesulfonic acid·monohydrate (200 mg)were added to the resulting oily product, and stirred at 140° C. for 4hours. After the reaction solution was cooled to ambient temperature,ethyl acetate was added to the reaction solution. The separated organiclayer was washed with aqueous 1 mol/liter sodium hydroxide solution anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The resulting residue was purified by silica gelchromatography (eluent: n-hexane/ethyl acetate=3/1–1/1), to afford theentitled compound3-benzyloxymethyl-5-biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazoleas pale yellow solid (6.60 g, 58%). The physico-chemical values are asfollows.

FAB-MS m/z: 436 (M⁺+H). ¹H-NMR (DMSO-d₆) δ: 4.35 (1H, d, J=11.9 Hz),4.40 (1H, d, J=11.9 Hz), 7.06–7.12 (2H, m), 7.23–7.52 (10H, m),7.62–7.73 (5H, m), 7.81 (1H, ddd, J=1.7, 8.0, 9.5 Hz).

Example 14[5-Biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl]methanol

3-Benzyloxymethyl-5-biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazole(6.00 g) was dissolved in chloroform (200 ml), followed by dropwiseaddition of 1 mol/liter boron trichloride-hexane solution (30 ml) at−44° C. and stirred at the same temperature for 30 minutes and atambient temperature for one hour. To the reaction solution were addedmethanol (5 ml) and saturated aqueous sodium hydrogen carbonate solution(50 ml), followed by concentration under reduced pressure. To theresulting residue were added tetrahydrofuran (100 ml), aqueous 2mol/liter sodium hydroxide solution (100 ml) andtetrabutylammoniumhydrogensulfate (0.10 g), and stirred at ambienttemperature for 12 hours. The reaction solution was extracted with ethylacetate, and the organic layer was dried over anhydrous magnesiumsulfate. After the solvent was evaporated under reduced pressure, theresulting residue was purified by silica gel chromatography (eluent:chloroform/methanol=96/4) and recrystallized from a mixture solution ofn-hexane-ethyl acetate-ethanol, to afford the entitled compound as whitecrystal (2.09 g, 44%). The physico-chemical values are as follows.

mp: 220–223° C. ¹H-NMR (DMSO-d₆) δ: 4.47 (1H, dd, J=5.5, 13.2 Hz), 4.53(1H, dd, J=5.5, 13.2 Hz), 5.46 (1H, t, J=5.5 Hz), 7.34–7.50 (7H, m),7.59–7.75 (5H, m), 7.79 (1H, ddd, J=1.5, 8.2, 9.7 Hz).

Example 153-Biphenyl-4-yl-5-chloromethyl-4-(2-fluorophenyl)-4H-1,2,4-triazole

[5-Biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl]methanol (1.81g) was suspended in toluene (25 ml), followed by addition of thionylchloride (1.5 ml) and chloroform (25 ml), and stirred at 60° C. for 5hours. After the reaction solution was concentrated under reducedpressure, ethyl acetate was added to the reaction solution, which waswashed with saturated aqueous sodium hydrogen carbonate solution. Afterthe organic layer was dried over anhydrous magnesium sulfate, thesolvent was evaporated under reduced pressure. The resulting white solidwas washed with a mixture solution of n-hexane and ethyl acetate, toafford the entitled compound as white solid (1.54 g, 81%). Thephysico-chemical values are as follows.

FAB-MS m/z: 364 (M⁺+H). ¹H-NMR (DMSO-d₆) δ: 4.80 (1H, d, J=13.0 Hz),4.87 (1H, d, J=13.0 Hz), 7.34–7.54 (7H, m), 7.66–7.75 (5H, m), 7.91 (1H,ddd, J=1.6, 6.2, 9.2 Hz).

Example 164-{[5-Biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl]methyl}morpholine

Morpholine (0.599 ml) was dissolved in N,N-dimethylformamide (6 ml),followed by addition of sodium hydride (60%, 275 mg) under ice cooling,and stirred at the same temperature for 30 minutes. Under ice cooling,3-biphenyl-4-yl-5-chloromethyl-4-(2-fluorophenyl)-4H-1,2,4-triazole (599mg) was added to the reaction solution, and stirred at ambienttemperature for 17 hours. After the reaction solution was concentratedunder reduced pressure, saturated aqueous sodium hydrogen carbonatesolution was added to the resulting residue, followed by extraction withchloroform. The organic layer was dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresulting residue was purified by silica gel chromatography (eluent:toluene/acetone=3/2 to 1/1), and recrystallized from a mixture solutionof n-hexane and ethyl acetate, to afford the entitled compound as whitecrystal (211 mg, 74%). The physico-chemical values are as follows.

mp: 129–131° C. ¹H-NMR (DMSO-d₆) δ: 2.13–2.26 (4H, m), 3.29–3.34 (4H,m), 3.50 (1H, d, J=14.2 Hz), 3.63 (1H, d, J=14.2 Hz), 7.36–7.51 (7H, m),7.60–7.70 (5H, m), 7.81–7.85 (1H, m).

The following Tables (2) and (3) show the structural formulas andphysico-chemical properties of the compounds of the Example.

In the tables, the abbreviation ‘Ex’ represents Example. Otherabbreviations are as described above.

(2)

Ex.

A′ Ra DATA: MS m/z 17 biphenyl-4-yl

Me M⁺ + H: 362 (FAB) 18 biphenyl-4-yl indan-2-yl Et M + H: 366 (FAB) 19biphenyl-4-yl cHex Et M⁺ + H: 332 (FAB) 20 biphenyl-4-yl morpholin-4-ylMe M⁺ + H: 321 (FAB) 21 biphenyl-4-yl 1H-pyrazol-3-yl Me M⁺ + H: 302(FAB) 22 biphenyl-4-yl 2-Ph-2H-pyrazol-3-yl Et M⁺ + H: 392 (FAB) 23biphenyl-4-yl 3-Me-pyridin-2-yl Me M⁺ + H: 327 (FAB) 24 biphenyl-4-ylpyridin-3-yl Me M⁺ + H: 313 (FAB) 25 biphenyl-4-yl 2-Cl-pyridin-3-yl MeM⁺ + H: 347 (FAB) 26 biphenyl-4-yl 6-Cl-pyridin-3-yl Me M⁺ + H: 347(FAB) 27 biphenyl-4-yl

Me M⁺ + H: 354 (FAB) 28 biphenyl-4-yl quinolin-8-yl Et M⁺ + H: 377 (FAB)29

2-F-Ph Me M⁺ + H: 321 (FAB) 30

2-F-Ph Me M⁺ + H: 336 (FAB) 31

2-F-Ph Me M⁺ + H: 351 (FAB) 32

2-F-Ph Me M⁺ + H: 351 (FAB) 33

2-F-Ph Me M⁺ + H: 331 (FAB) 34

2-F-Ph Me M⁺ + H: 331 (FAB) 35 biphenyl-4-yl

Et M⁺ + H: 368 (FAB) 36 biphenyl-4-yl

Me₂CH— M⁺ + H: 382 (FAB) 37 biphenyl-4-yl

Et M⁺ + H: 384 (FAB) 38 biphenyl-4-yl

Et M⁺ + H: 366 (FAB) 39 biphenyl-4-yl

Et M⁺ + H: 380 (FAB) 40 biphenyl-4-yl

Et M⁺ + H: 376 (FAB) 41 biphenyl-4-yl

Et M⁺ + H: 376 (FAB) 42 biphenyl-4-yl

Et M⁺ + H: 365 (FAB) 43 biphenyl-4-yl

Et M⁺ + H: 379 (FAB) 44 biphenyl-4-yl

Et M⁺ + H: 366 (FAB) 45 biphenyl-4-yl

Et M⁺ + H: 366 (FAB) 46 biphenyl-4-yl

Et M⁺ + H: 366 (FAB) 47 biphenyl-4-yl

Et M⁺ + H: 366 (FAB) 48 biphenyl-4-yl

Et M⁺ + H: 366 (FAB) 49 biphenyl-4-yl

Et M⁺ + H: 381 (FAB) 50 biphenyl-4-yl

Et M⁺ + H: 391 (FAB) 51 biphenyl-4-yl

Et M⁺ + H: 391 (FAB) 52 biphenyl-4-yl

Et M⁺ + H: 377 (FAB) 53 biphenyl-4-yl

Et M⁺ + H: 377 (FAB) 54 biphenyl-4-yl

Me(CH₂)₂— M⁺ + H: 391 (FAB) 55 biphenyl-4-yl

MeO(CH₂)₃— M⁺ + H: 421 (FAB) 56 biphenyl-4-yl

Et M⁺ + H: 393 (FAB) 57 biphenyl-4-yl

Et M⁺ + H: 411 (FAB) 58 biphenyl-4-yl

Et M⁺ + H: 411 (FAB) 59 biphenyl-4-yl

Et M⁺ + H: 411 (FAB) 60 biphenyl-4-yl

Et M⁺ + H: 393 (FAB) 61 biphenyl-4-yl

Et M⁺ + H: 381 (FAB) 62 biphenyl-4-yl

Et M⁺ + H: 395 (FAB) 63 biphenyl-4-yl

Me₂CH— M⁺ + H: 391 (FAB) 64 biphenyl-4-yl

Et M⁺ + H: 377 (FAB) 65 biphenyl-4-yl Et M⁺ + H: 377 (FAB) 66biphenyl-4-yl

Et M⁺ + H: 377 (FAB) 67 biphenyl-4-yl

Et M⁺ + H: 377 (FAB) 68

2-F-Ph Et M⁺ + H: 351 (FAB) 69

2-F-Ph Et M⁺ + H: 349 (FAB) 70

2-F-Ph Et M⁺ + H: 351 (FAB) 71

2-F-Ph Et M⁺ + H: 352 (FAB) 72

2-F-Ph Et M⁺ + H: 345 (FAB) 73

2-F-Ph Et M⁺ + H: 345 (FAB) 74

2-F-Ph Me₂CH— M⁺ + H: 359 (FAB) 75

2-F-Ph MeO(CH₂)₃— M⁺ + H: 389 (FAB) 76

2-F-Ph Me₂N— M⁺ + H: 360 (FAB) 77

2-F-Ph EtNH— M⁺ + H: 360 (FAB) 78

2-F-Ph

M⁺ + H: 390 (FAB) 79

2-F-Ph

M⁺ + H: 404 (FAB) 80

2-F-Ph

M⁺ + H: 418 (FAB) 81

2-F-Ph

M⁺ + H: 432 (FAB) 82

2-F-Ph

M⁺ + H: 416 (FAB) 83

2-F-Ph

M⁺ + H: 416 (FAB) 84

2-F-Ph

M⁺ + H: 416 (FAB) 85

2-F-Ph Et M⁺ + H: 361 (FAB) 86

2-F-Ph Et M⁺ + H: 379 (FAB) 87

2-F-Ph Et M⁺ + H: 379 (FAB) 88

2-F-Ph Et M⁺ + H: 388 (FAB) 89

2-F-Ph Et M⁺ + H: 421 (FAB) 90

2-CN-Ph Et M⁺ + H: 352 (FAB) 91

2-CN-Ph Me₂CH— M⁺ + H: 366 (FAB) 92

2-CN-Ph MeO(CH₂)₃— M⁺ + H: 396 (FAB) 93

2-CN-Ph Me₂N- M⁺ + H: 367 (FAB) 94

2-CN-Ph

M⁺ + H: 437 (FAB) 95

Et M⁺ + H: 386 (FAB) 96

Me₂CH— M⁺ + H: 400 (FAB) 97

MeO(CH₂)₃— M⁺ + H: 430 (FAB) 98

Me₂CH— M⁺ + H: 380 (FAB) 99

EtNH— M⁺ + H: 381 (FAB) 100

M⁺ + H: 411 (FAB) 101

M⁺ + H: 425 (FAB) 102

M⁺ + H: 437 (FAB) 103

Me₂CH— M⁺ + H: 369 (ESI) 104

Me₂CH— M⁺ + H: 409 (ESI) 105

MeO(CH₂)₃— M⁺ + H: 407 (FAB) 106

M⁺ + H: 419 (FAB) 107

M⁺ + H: 433 (FAB) 108

H₂N— M⁺ + H: 350 (FAB) 109

CF₃CH₂— M⁺ + H: 417 (FAB) 110

CF₃CF₂— M⁺ + H: 453 (FAB) 111

CF₃(CH₂)₂— M⁺ + H: 431 (FAB) 112

Me₂CH— M⁺ + H: 411 (FAB) 113

Me₂CH— M⁺ + H: 394 (FAB) 114

Me₂CH— M⁺ + H: 395 (FAB) 115

Me₂CH— M⁺ + H: 395 (FAB) 116

MeO(CH₂)₃— M⁺ + H: 413 (FAB) 117

Me₂N— M⁺ + H: 384 (FAB) 118

Et M⁺ + H: 378 (FAB) 119

Me(CH₂)₂— M⁺ + H: 392 (FAB) 120

Me₂CH— M⁺ + H: 392 (FAB) 121

MeO(CH₂)₃— M⁺ + H: 422 (FAB) 122

MeNH— M⁺ + H: 379 (FAB) 123

EtNH— M⁺ + H: 393 (FAB) 124

Me₂N— M⁺ + H: 393 (FAB) 125

M⁺ + H: 423 (FAB) 126

M⁺ + H: 437 (FAB) 127

M⁺ + H: 449 (FAB)

(3)

Ex Ra Rb (Rc)p Rd′ Re′ DATA: MS m/z 128 MeOCH₂— 2-F — H H M⁺ + H: 360(FAB) 129 HO₂CCH₂N(Me)CH₂— 2-F — H H M⁺ + H: 417 (FAB) 130MeO₂CCH₂N(Me)CH₂— 2-F — H H M⁺ + H: 431 (FAB) 131 furan-2-yl 2-F — H HM⁺ + H: 382 (FAB) 132 MeS- 2-OMe — H H M⁺ + H: 374 (FAB) 133 EtS- 2-OMe— H H M⁺ + H: 388 (FAB) 134 Me(CH₂)₂S— 2-F — H H M⁺ + H: 390 (FAB) 135Me(CH₂)₄S— 2-F — H H M⁺ + H: 418 (FAB) 136 Me(CH₂)₆S— 2-F — H H M⁺ + H:446 (FAB) 137 CH₂═CHCH₂S— 2-F — H H M⁺ + H: 388 (FAB) 138 CH≡CCH₂S 2-F —H H M⁺ + H: 386 (FAB) 139 cHex-CH₂—S— 2-F — H H M⁺ + H: 444 (FAB) 140cPr-CH₂—S— 2-F — H H M⁺ + H: 402 (FAB) 141 NCCH₂S— 2-F — H H M⁺ + H: 387(FAB) 142 PhCH₂S— 2-F — H H M⁺ + H: 438 (FAB) 143 (2,6-di-Cl-Ph)CH₂S—2-F — H H M⁺ + H: 506 (FAB) 144 (2-OMe-5-NO₂-Ph)CH₂S— 2-F — H H M⁺ + H:513 (FAB) 145 (4-CO₂Me-Ph)CH₂S— 2-F — H H M⁺ + H: 496 (FAB) 1462-Py-CH₂—S— 2-F — H H M⁺ + H: 439 (FAB) 147 3-Py-CH₂—S— 2-F — H H M⁺ +H: 439 (FAB) 148 4-Py-CH₂—S— 2-F — H H M⁺ + H: 439 (FAB) 149 Ph(CH₂)₂S—2-F — H H M⁺ + H: 452 (FAB) 150 H₂NC(O)CH₂S— 2-F — H H M⁺ + H: 405 (FAB)151 Et₂N(CH₂)₂S— 2-F — H H M⁺ + H: 447 (FAB) 152 Me₂CHS— 2-F — H H M⁺ +H: 390 (FAB) 153 MeC(O)CH₂S— 2-F — H H M⁺ + H: 404 (FAB) 154 HO₂CCH₂S—2-F — H H M⁺ + H: 406 (FAB) 155 Et₂NC(O)CH₂S— 2-F — H H M⁺ + H: 461(FAB) 156 2-Qin-CH₂—S— 2-F — H H M⁺ + H: 489 (FAB) 157HO₂CCH₂N(Me)(CH₂)₃S— 2-F — H H M⁺ + H: 477 (FAB) 158 Me2-HO₂CCH₂N(Me)(CH₂)₃O— — H H M⁺ + H: 457 (FAB) 159 Me 2-CF₃ — H H M⁺ +H: 380 (FAB) 160 Me 2-OCF₃ — H H M⁺ + H: 395 (FAB) 161 Me 2-CO₂H — H HM⁺ + H: 356 (FAB) 162 Me 2-CONH₂ — H H M⁺ + H: 355 (FAB) 163 Me 2-CONMe₂— H H M⁺ + H: 383 (FAB) 164 Me 2-pyrrol-1-yl — H H M⁺ + H: 377 (FAB) 165Me 2-imidazol-1-yl — H H M⁺ + H: 378 (FAB) 166 Me 2-(1H-tetrazol-5-yl) —H H M⁺ + H: 380 (FAB) 167 Me 2-S(O)Me — H H M⁺ + H: 374 (FAB) 168 Me2-SO₂Me — H H M⁺ + H: 390 (FAB) 169 Me 2-SO₂Ph — H H M⁺ + H: 452 (FAB)170 Me 2-OMe — H 3-F M⁺ + H: 360 (ESI) 171 Me 2-OMe — H 4-F M⁺ + H: 360(ESI) 172 Me 2-OMe — H 2-Cl M⁺ + H: 376 (ESI) 173 Me 2-OMe — H 3-Cl M⁺ +H: 376 (ESI) 174 Me 2-OMe — H 4-Cl M⁺ + H: 376 (ESI) 175 Me 2-OMe — H2-OMe M⁺ + H: 372 (ESI) 176 Me 2-OMe — H 3-OMe M⁺ + H: 372 (ESI) 177 Me2-OMe — H 3-OEt M⁺ + H: 386 (ESI) 178 Me 2-OMe — H 4-OMe M⁺ + H: 372(ESI) 179 Me 2-OMe — H 4-CF₃ M⁺ + H: 410 (ESI) 180 Me 2-OMe — H 4-OCF₃M⁺ + H: 426 (ESI) 181 Me 2-OMe — H 3-NHAc M⁺ + H: 399 (ESI) 182MeO(CH₂)₂— 2-F — H H M⁺ + H: 374 (FAB) 183 MeO(CH₂)₃— 2-F — H H M⁺ + H:388 (FAB) 184 HO(CH₂)₂— 2-F — H H M⁺ + H: 360 (FAB) 185 HO(CH₂)₃— 2-F —H H M⁺ + H: 374 (FAB) 186 HO₂CCH₂N(Me)(CH₂)₂— 2-F — H H M⁺ + H: 431(FAB) 187 HO₂CCH₂N(Me)(CH₂)₃— 2-F — H H M⁺ + H: 445 (FAB) 188

2-F — H H M⁺ + H: 402 (FAB) 189

2-F — H H M⁺ + H: 388 (FAB) 190 NCCH₂— 2-F — H H M⁺ + H: 355 (FAB) 191NC(CH₂)₂— 2-F — H H M⁺ + H: 369 (FAB) 192

2-F — H H M⁺ + H: 367 (FAB) 193 Ph-NH—CH₂— 2-F — H H M⁺ + H: 421 (FAB)194 Ph-N(Me)—CH₂— 2-F — H H M⁺ + H: 435 (FAB) 195 3-Py-O-CH₂— 2-F — H HM⁺ + H: 423 (FAB) 196 imidazol-1-yl-CH₂— 2-F — H H M⁺ + H: 396 (FAB) 197Et₂NCH₂— 2-F — H H M⁺ + H: 401 (FAB) 198

2-F — H H M⁺ + H: 413 (FAB) 199

2-F — H H M⁺ + H: 415 (FAB) 200

2-F — H H M⁺ + H: 461 (FAB) 201

2-F — H H M⁺ + H: 461 (FAB) 202

2-F — H H M⁺ + H: 467 (FAB) 203

2-F — H H M⁺ + H: 414 (FAB) 204

2-F — H H M⁺ + H: 386 (FAB) 205

2-F — H H M⁺ + H: 489 (FAB) 206

2-F — H H M⁺ + H: 399 (FAB) 207 H₂N— 2-F — H H M⁺ + H: 331 (FAB) 208MeNH— 2-F — H H M⁺ + H: 345 (FAB) 209 EtNH— 2-F — H H M⁺ + H: 359 (FAB)210 Me(CH₂)₂NH— 2-F — H H M⁺ + H: 373 (FAB) 211 Me(CH₂)₃NH— 2-F — H HM⁺ + H: 387 (FAB) 212 Me₂CHNH— 2-F — H H M⁺ + H: 373 (FAB) 213

2-F — H H M⁺ + H: 387 (FAB) 214

2-F — H H M⁺ + H: 385 (FAB) 215

2-F — H H M⁺ + H: 399 (FAB) 216

2-F — H H M⁺ + H: 413 (FAB) 217

2-F — H H M⁺ + H: 402 (FAB) 218

2-F — H H M⁺ + H: 405 (FAB) 219

2-F — H H M⁺ + H: 375 (FAB) 220

2-F — H H M⁺ + H: 389 (FAB) 221

2-F — H H M⁺ + H: 403 (FAB) 222

2-F — H H M⁺ + H: 417 (FAR) 223

2-F — H H M⁺ + H: 403 (FAB) 224

2-F — H H M⁺ + H: 417 (FAB) 225

2-F — H H M⁺ + H: 431 (FAB) 226

2-F — H H M⁺ + H: 403 (FAB) 227

2-F — H H M⁺ + H: 417 (FAB) 228

2-F — H H M⁺ + H: 431 (FAB) 229

2-F — H H M⁺ + H: 403(FAR) 230

2-F — H H M⁺ + H: 417 (FAB) 231

2-F — H H M⁺ + H: 403 (FAB) 232

2-F — H H M⁺ + H: 401 (FAB) 233

2-F — H H M⁺ + H: 415 (FAB) 234

2-F — H H M⁺ + H: 415 (FAB) 235

2-F — H H M⁺ + H: 415 (FAB) 236

2-F — H H M⁺ + H: 429 (FAB) 237

2-F — H H M⁺ + H: 415 (FAB) 238

2-F — H H M⁺ + H: 443 (FAB) 239

2-F — H H M⁺ + H: 422 (FAB) 240

2-F — H H M⁺ + H: 422 (FAB) 241 Me₂N— 2-F — H H M⁺ + H: 359 (FAB) 242Et₂N— 2-F — H H M⁺ + H: 387 (FAB) 243

2-F — H H M⁺ + H: 373 (FAB) 244

2-F — H H M⁺ + H: 401 (FAB) 245

2-F — H H M⁺ + H: 382 (FAB) 246

2-F — H H M⁺ + H: 396 (FAB) 247 CH₃CONH— 2-F — H H M⁺ + H: 373 (FAB) 248CH₃SO₂NH— 2-F — H H M⁺ + H: 409 (FAB) 249 MeO— 2-F — H H M⁺ + H: 346(FAB) 250 EtO— 2-F — H H M⁺ + H: 360 (FAB) 251 MeS— 2-F — H H M⁺ + H:362 (FAB) 252 EtS— 2-F — H H M⁺ + H: 376 (FAB) 253 MeSO₂— 2-F — H H M⁺ +H: 394 (FAB) 254 Me 3-CF₃ — H H M⁺ + H: 380 (FAB) 255 Et 3-CF₃ — H HM⁺ + H: 394 (FAB) 256 Me 2-NO₂ — H H M⁺ + H: 357 (FAB) 257 Me 2-NHOH — HH M⁺ + H: 343 (FAB) 258 Me 2-NHCOMe — H H M⁺ + H: 369 (FAB) 259 Me2-NHCOPh — H H M⁺ + H: 431 (FAB) 260 Me 2-2-NHSO₂Me — H H M⁺ + H: 405(FAB) 261 Me 2-NHSO₂Ph — H H M⁺ + H: 467 (FAB) 262 Me 2-CO₂Me — H H M⁺ +H: 370 (FAB) 263 Me₂CH— 2-CO₂Me — H H M⁺ + H: 398 (FAB) 264

2-Br — H H M⁺ + H: 463 (FAB) 265

2-Br — H H M⁺ + H: 475 (FAB) 266 Me 2-CN — H H M⁺ + H: 337 (FAB) 267 Et2-CN — H H M⁺ + H: 351 (FAB) 268 Me₂N— 2-CN — H H M⁺ + H: 366 (FAB) 269

2-CN — H H M⁺ + H: 410 (FAB) 270 Et 3-CN — H H M⁺ + H: 351 (FAB) 271 Et3-NHCOMe 2-Me H H M⁺ + H: 397 (FAB) 272 Et 3-COOMe 2-Me H H M⁺ + H: 398(FAB) 273 Et 3-CONH₂ 2-Me H H M⁺ + H: 383 (FAB) 274 Et 3-CH₂-OH 2-Me H HM⁺ + H: 370 (FAB) 275 Et 3-CH₂OMe 2-Me H H M⁺ + H: 384 (FAB) 276 Et3-CH₂NMe₂ 2-Me H H M⁺ + H: 397 (FAB) 277 Et 3-CH₂-CN 2-Me H H M⁺ + H:379 (FAB) 278 Et 3-CONH₂ 2-Cl H H M⁺ + H: 403 (FAB) 279 Et 2-(3-Py-O-) —H H M⁺ + H: 419 (FAB) 280 Et 2-(2-Py-O-) — H H M⁺ + H: 419 (FAB) 281 Et—2-F — 2-OMe H M⁺ + H: 374 (FAB) 282 Et— 2-F — 2-OH H M⁺ + H: 360 (FAB)283 Et— 2-F — 3-OMe H M⁺ + H: 374 (FAB) 284 Et— 2-F — 3-OH H M⁺ + H: 360(FAB) 285 CF₃— 2-F — H H M⁺ + H: 384 (FAB) 286 CF₃— 2-F — 2-OMe H M⁺ +H: 414 (FAB) 287 CF₃— 2-F — 3-Me H M⁺ + H: 398 (FAB) 288 CF₃CH₂— 2-F — HH M⁺ + H: 398 (FAB)

INDUSTRIAL APPLICABILITY

The pharmaceutical drug of the invention has an action to inhibit theactivity of glycine transporter and an activity to activate the functionof the NMDA receptor. Thus, the pharmaceutical drug of the invention isuseful as a therapeutic agent of dementia, schizophrenia, cognitivedisorders, or cognitive disorders involved in various diseases such asAlzheimer disease, Parkinson's disease or Huntington disease or thelike, or spasm involved in diseases such as nerve degenerative diseasesand cerebrovascular disorders, or the like. Particularly, thepharmaceutical drug is useful for the amelioration of learningdisability of dementia and the like.

1. A pharmaceutical composition for glycine transporter inhibitor whichcomprises a triazole compound represented by the following formula (I)or a pharmaceutically acceptable salt thereof as the effectiveingredient:

in the formula, the symbols represent the following meanings; Ring A:(1) an aromatic carbon ring which may be substituted, (2) an aliphaticcarbon ring which may be substituted and may be condensed with benzenering or hetero ring, or (3) a 6-membered hetero ring which may besubstituted and contain one nitrogen atom as a ring atom and may containone oxygen atom or sulfur atom as a hetero atom other than the nitrogenatom and may be condensed with benzene ring; Ring B or D may be the sameor different and each represents aromatic carbon ring which may besubstituted, an aliphatic carbon atom which may be substituted, or ahetero ring which may be substituted; R: H, halogeno-lower alkyl, arylwhich may be substituted, hetero ring which may be substituted,cycloalkyl which may be substituted, or -[Alk1]m-X-[Alk2]n-Y—R¹ whereinR¹: H, OH, cyano, aryl which may be substituted, hetero ring which maybe substituted, cycloalkyl which may be substituted, or lower alkoxyl;X: bond, oxygen atom, S(O)q, or —N(R²)—; Y: bond, —C(O)—, —C(O)—N(R³)—,-Z₁-Alk3-, or —N(R³)—Alk3-C(O)—, with the proviso that R¹ representother than OH and lower alkoxy, when Y is bond; Alk1 or Alk2 may be thesame or different and each represents lower alkylene, lower alkenyleneor lower alkynylene; and m or n may be the same or different and eachrepresents 0 or 1 or m+n=1, provided that X represents bond; Z₁: S(O)q,—N(R³)—, —C(O)— or —C(O)—N(R³)—; Alk3: lower alkylene; R² or R³: thesame or different from each other and each represents H or lower alkyl;q: may be 0, 1 or
 2. 2. A pharmaceutical composition for amelioratinglearning disability according to claim
 1. 3. A triazole compoundrepresented by the following formula (Ia) or a salt thereof:

in the formula, the symbols represent the following meanings; Ring A′:(1) the group represented by the formula:

(2) naphthalene which may be substituted with one or two substituentsselected from the group represented by Rf, (3) an aliphatic carbon ringwhich may be substituted with one or two substituents selected from thegroup represented by Rf and which may be condensed with benzene ring orhetero ring, or (4) a 6-membered hetero ring which may be substitutedwith one or two substituents selected from the group represented by Rfand which contain one nitrogen atom as the ring atom and may contain oneoxygen atom or sulfur atom as a hetero atom other than the nitrogen atomand may be condensed with benzene ring; Ring B′: benzene ornitrogen-containing monocyclic hetero ring; or Ring D′: benzene orhetero ring, provided that ring A′, B′ and D′ never simultaneouslyrepresents benzene ring; Ra: a halogeno-lower alkyl, a hetero ring whichmay be substituted, cycloalkyl which may be substituted, or-[Alk1]m-X-[Alk2]n-Y—R¹ wherein R¹: H, OH, cyano, aryl which may besubstituted, hetero ring which may be substituted, cycloalkyl which maybe substituted, or lower alkoxyl; X: bond, oxygen atom, S(O)q, or—N(R²)—; Y: bond, —C(O)—, —C(O)—N(R³)—, -Z₁-Alk3-, or —N(R³)-Alk3—C(O)—,with the proviso that R¹ represent other than OH and lower alkoxy, whenY is bond; Alk1 or Alk2 may be the same or different and each representslower alkylene, lower alkenylene, or lower alkynylene; m or n may be thesame or different and each represents 0 or 1 or m+n=1, provided that Xrepresents bond; Z₁: S(O)q, —N(R³)—, —C(O)— or —C(O)—N(R³)—; Alk3: loweralkynylene; R² or R³: the same or different from each other and eachrepresents H, or lower alkyl; Rb: halogen atom, lower alkyl which may besubstituted with the following substituents, lower alkynyl,halogeno-lower alkyl, hetero ring, hetero ring-O—, cyano, nitro,halogeno-lower alkyl-O—, lower alkoxyl, —O-lower alkylene-N(R³)-loweralkylene-C(O)O—R⁶, Z₂-R⁶, or Z₃-R⁷, the substituents of the lower alkyl:OH, cyano, lower alkoxyl, amino which may be substituted with loweralkyl; Z₂: S(O)q, —N(R³)—, —C(O)—, —C(O)—N(R³)—, —N(R³)—C(O)—,—C(O)—S(O)q-, —N(R³)—S(O) q-, or —C(O)O—; Z₃: —N(R³)—, or —N(R³)—C(O)—;R⁶: H, lower alkyl or aryl; R⁷: OH, or lower alkoxyl; p: 0 or 1; q: 0, 1or 2; Rc: lower alkyl, or halogen atom; Rd or Re: the same or differentfrom each other and each represents H, halogen atom, lower alkyl, loweralkoxyl, OH, lower alkyl, halogeno-lower alkyl, phenyl, halogeno-loweralkyl-O—, amino which may be substituted with lower alkyl or—NR⁸C(O)—R⁹; R⁸ or R⁹: the same or different from each other and eachrepresents H, or lower alkyl; Rf: a group represented by Rb, oxo group,or aryl, with the proviso that Rd represents other than H, when the ringA′ represents benzene substituted with lower alkoxyl and the ring B′represents benzene.
 4. A triazole compound represented by the followingformula (Ib) or a salt thereof:

in the formula, the symbols represent the following meanings: Ra: ahalogeno-lower alkyl, a hetero ring which may be substituted, cycloalkylwhich may be substituted, or -[Alk1]m-X-[Alk2]n-Y—R¹ wherein R¹: H, OH,cyano, aryl which may be substituted, hetero ring which may besubstituted, cycloalkyl which may be substituted, or lower alkoxyl; X:bond, oxygen atom, S(O)q, or —N(R²)—; Y: bond, —C(O)—, —C(O)—N(R³)—,-Z₁-Alk3-, or —N(R³)—Alk3-C(O)—, with the proviso that R¹ representother than OH and lower alkoxy, when Y is bond; Alk1 or Alk2 may be thesame or different and each represents lower alkylene, lower alkenylene,or lower alkynylene; m or n may be the same or different and eachrepresents 0 or 1 or m+n=1, provided that X represents bond; Z₁: S(O)q,—N(R³)—, —C(O)— or —C(O)—N(R³)—; Alk3: lower alkynylene; R² or R³: thesame or different from each other and each represents H, or lower alkyl;Rb′: halogen atom, lower alkyl which may be substituted with thefollowing substituents, halogeno-lower alkyl, hetero ring, heteroring-O—, cyano, nitro, halogeno-lower alkyl-O—, lower alkoxyl, —O-loweralkylene-N(R³)-lower alkylene-C(O)O—R⁶, —N(R³)—R⁷, Z₂′-R⁶, or Z₃-R⁷; thesubstituents of the lower alkyl: OH, cyano, lower alkoxyl, amino whichmay be substituted with lower alkyl; Z₂′: S(O)q, —C(O)—, —C(O)—N(R³)—,—N(R³)—C(O)—, —C(O)—S(O)q-, —N(R³)—S(O)q-, —C(O)O; Z₃: —N(R³)—, or—N(R³)—C(O)—; R⁶: H, lower alkyl or aryl; R⁷: OH, or lower alkoxyl; p: 0or 1; q: 0, 1 or 2; Rc: lower alkyl, or halogen atom; Rd′: H, loweralkoxyl, OH or lower alkyl; Re′: H, halogen atom, lower alkoxyl,halogeno-lower alkyl, halogeno-lower alkyl-O—, or NR⁸C(O)—R⁹; R⁸ or R⁹:the same group as formula (Ia) described in the claim 3; with theproviso that, (1) at least one of Rd′ or Re′ represents a group otherthan H, when Ra is lower alkyl, p=0: Rb′ represents lower alkyl, loweralkoxyl or halogen atom; or Rd′ represents a group except for loweralkyl, provided that Re′ is H; (2) Rb′ represents a group other thanlower alkyl or lower alkoxyl, when Ra represents α-styrly and Rd′ andRe′ represent H and p=0; (3) Rb′ represents a group other than loweralkyl, when Ra represents 2 furyl and Rd′ and Re′ represent H and p=0.5. A triazole compound or a salt thereof according to claim 3, whereinin the triazole derivative represented by the general formula (Ia), thering B′ represents nitrogen-containing monocyclic hetero ring; the ringD′ is benzene ring; Rf is halogen atom, lower alkyl, lower alkoxyl,aryl, cyano, carbamoyl or oxo group.
 6. A compound selected from thegroup consisting of5-[4-(2,6-Difluorophenyl)-5-isopropyl-4H-1,2,4-triazol-3-yl]-2-phenylpyridine;4-[3-isopropyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzooxadiazole;3-[3-(3-methoxypropyl)-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile;3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile;2-{3-[N-(2-methoxyethyl)-N-methylamino]-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl}benzonitrile;and4-(2,1,3-benzooxadiazol-4-yl)-N-(2-methoxyethyl)-N-methyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-3-ylamineor a salt thereof.
 7. A pharmaceutical composition which comprises thetriazole compound of claim 3 or 4 as an active ingredient.